Inhibitors of poly(ADP-ribose)polymerase

ABSTRACT

Inhibitors of poly(ADP-ribose)polymerase, ways to make them and methods of treating patients using them are disclosed.

This application is a continuation application of U.S. patentapplication Ser. No. 12/138,168, filed Jun. 12, 2008, now U.S. Pat. No.8,466,150, which is a continuation-in-part of U.S. patent applicationSer. No. 11/964,822, filed Dec. 27, 2007, which claims priority fromProvisional U.S. patent application Ser. No. 60/882,317, filed Dec. 28,2006, all of which are incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to inhibitors of poly(ADP-ribose)polymerase, waysto make them and methods of treating patients using them.

BACKGROUND OF THE INVENTION

Poly(ADP-ribose)polymerase (PARP) is essential for facilitating DNArepair, controlling RNA transcription, mediating cell death andregulating immune response. This activity makes PARP inhibitors targetsfor a number of disorders. PARP inhibitors have shown utility fortreating diseases such as ischemia reperfusion injury, inflammatorydisease, retroviral infections, ischemia reperfusion injury, myocardialinfarction, stroke and other neural trauma, organ transplantation,reperfusion of the eye, kidney, gut and skeletal muscle, arthritis,gout, inflammatory bowel disease, CNS inflammation such as MS andallergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, and uveitis, diabetes and Parkinsons disease, livertoxicity following acetominophen overdose, cardiac and kidney toxicitiesfrom doxorubicin and platinum-based antineoplastic agents and skindamage secondary to sulfur mustards. PARP inhibitors have also beenshown to potentiate radiation and chemotherapy by increasing cell deathof cancer cells, limiting tumor growth, decreasing metastasis, andprolonging the survival of tumor-bearing animals.

US 2002/0183325 A1 describes phthalazinone derivatives as PARPinhibitors. US 2004/0023968 A1 describes phthalazinone derivatives asPARP inhibitors. US 2005/0085476 A1 describes fused pyridazinederivatives as PARP inhibitors. US 2005/0059663 A1 describesphthalazinone derivatives as PARP inhibitors. US 2006/0063767 A1describes phthalazinone derivatives as PARP inhibitors. US 2006/0142293A1 describes phthalazinone derivatives as PARP inhibitors. US2006/0149059 A1 describes phthalazinone derivatives as PARP inhibitors.US 2007/0093489 A1 describes phthalazinone derivatives as PARPinhibitors.

There is therefore a need in the therapeutic arts for PARP inhibitors.Such compounds can be used to treat subjects suffering from cancer, andcan further expand the range of treatment options available for suchsubjects.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds thatinhibit the activity of poly(ADP-ribose) polymerase and have formula I

and pharmaceutically acceptable salts thereof, wherein

A¹ is R¹ or R², wherein A¹ is unsubstituted or substituted with one ortwo OH, CN, C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl,cycloalkane, OR^(A) or NR^(A)R^(A);

R^(A) is H or alkyl;

R¹ is cycloalkane or cycloalkene each of which is unfused or fused withR^(1A);

R^(1A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R² is heterocycloalkane or heterocycloalkene; each of which is unfusedor fused with R^(2A);

R^(2A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

A² is OR⁴, NHR⁴, N(R⁴)₂, SR⁴, S(O)R⁴, SO₂R⁴ or R⁵;

wherein each R⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl; each of which issubstituted with R¹⁰;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl or C₅-alkyl; each of whichis substituted with R¹⁰, and further unsubstituted or substituted withone or two or three of independently selected OR¹⁰, NHR¹⁰, N(R¹⁰)₂,SR¹⁰, S(O)R¹⁰, SO₂R¹⁰ or CF₃;

wherein each R¹⁰ is R^(10A), R^(10B) or R^(10C); each of which must beattached at a carbon atom;

R^(10A) is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R^(10C) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein each R¹⁰ is independently unsubstituted or substituted with oneor two or three of independently selected, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹,SO₂R¹¹, NH₂, NHR¹¹, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NR¹¹C(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹,NR¹¹C(O)OR¹¹, NHSO₂NH₂, NHSO₂NHR¹¹, NHSO₂N(R¹¹)₂, SO₂NH₂, SO₂NHR¹¹,SO₂N(R¹¹)₂, NHC(O)NH₂, NHC(O)NHR¹¹, NHC(O)N(R¹¹)₂, NR¹¹C(O)N(R¹¹)₂, NO₂,OH, (O), C(O)H, C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I;

wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹³ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁵ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NH₂, C(O)NHR¹⁶,C(O)N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHC(O)OR¹⁶, NR¹⁶C(O)OR¹⁶, OH, F,Cl, Br or I;

wherein each R¹⁶ is R¹⁷ or R^(17A);

R¹⁷ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁸, C(O)OH, NH₂,NHR¹⁸ or N(R¹⁸)₂, C(O)R¹⁸, C(O)NH₂, C(O)NHR¹⁸, C(O)N(R¹⁸)₂, NHC(O)R¹⁸,NR¹⁸C(O)R¹⁸, F, Cl, Br or I;

R^(17A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each R¹⁸ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

wherein each of the moieties represented by R¹², R¹³, R¹⁴, R^(17A), andR¹⁸ are independently unsubstituted or substituted with one or two orthree or four of independently selected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, OC(O)R¹⁹, OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹)₂,NHC(O)R¹⁹, NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹, NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹,NR¹⁹C(O)OR¹⁹, NHC(O)NH₂, NHC(O)NHR¹⁹, NHC(O)N(R¹⁹)₂, NR¹⁹(O)NHR¹⁹,NR¹⁹C(O)N(R¹⁹)₂, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹,C(O)NHSO₂R¹⁹, C(O)NR¹⁹SO₂R¹⁹, SO₂NH₂, SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR¹⁹, C(N)N(R¹⁹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³;

R²⁰ is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²² is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²³ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R²⁴, OR²⁴, SR²⁴,S(O)₂R²⁴, C(O)OH, NH₂, NHR²⁴N(R²⁴)₂, C(O)R²⁴, C(O)NH₂, C(O)NHR²⁴,C(O)N(R²⁴)₂, NHC(O)R²⁴, NR²⁴C(O)R²⁴, NHC(O)OR²⁴, NR²⁴C(O)OR²⁴,NHS(O)₂R²⁴, NR²⁴S(O)₂R²⁴, OH, F, Cl, Br or I;

wherein each R²⁴ is R^(24A) or R^(24B);

R^(24A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl each of which is unfused or fusedwith benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkaneor heterocycloalkene;

R^(24B) is alkyl, alkenyl or alkynyl each of which is unsubstituted orsubstituted with one or two of independently selected R²⁵, OR²⁵, SR²⁵,S(O)₂R²⁵, C(O)OH, NH₂, NHR²⁵N(R²⁵)₂, C(O)R²⁵, C(O)NH₂, C(O)NHR²⁵,C(O)N(R²⁵)₂, NHC(O)R²⁵, NR²⁵C(O)R²⁵, NHC(O)OR²⁵, NR²⁵C(O)OR²⁵, OH, F,Cl, Br or I;

wherein each R²⁵ is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl; each of which is unsubstitutedor substituted with NH₂, NH(CH₃), N(CH₃)₂, OH or OCH₃;

wherein each of the moieties represented by R²⁰, R²¹, R²², and R^(24A)are independently unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶, alkenyl, alkynyl, phenyl, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I; and

R²⁶ is alkyl.

Still another embodiment comprises pharmaceutical compositionscomprising a compound having formula I and an excipient.

Still another embodiment comprises methods of inhibiting PARP in amammal comprising administering thereto a therapeutically acceptableamount of a compound having formula I.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having formula I

or a salt thereof, wherein

A¹ is R¹ or R², wherein A¹ is unsubstituted or substituted with one ortwo OH, CN, C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl,cycloalkane, OR^(A) or NR^(A)R^(A);

R^(A) is H or alkyl;

R¹ is cycloalkane or cycloalkene each of which is unfused or fused withR^(1A);

R^(1A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R² is heterocycloalkane or heterocycloalkene; each of which is unfusedor fused with R^(2A);

R^(2A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

A² is OR⁴, NHR⁴, N(R⁴)₂, SR⁴, S(O)R⁴, SO₂R⁴ or R⁵;

wherein each R⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl; each of which issubstituted with R¹⁰;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl or C₅-alkyl; each of whichis substituted with R¹⁰, and further unsubstituted or substituted withone or two or three of independently selected OR¹⁰, NHR¹⁰, N(R¹⁰)₂,SR¹⁰, S(O)R¹⁰, SO₂R¹⁰ or CF₃;

wherein each R¹⁰ is R^(10A), R^(10B) or R^(10C); each of which must beattached at a carbon atom;

R^(10A) is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R^(10C) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein each R¹⁰ is independently unsubstituted or substituted with oneor two or three of independently selected, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹,SO₂R¹¹, NH₂, NHR¹¹, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NR¹¹C(O)R¹¹, NHSO₂R¹¹), NR¹¹SO₂R¹¹,NHC¹¹(O)OR¹¹, NR¹¹C(O)OR¹¹, NHSO₂NH₂, NHSO₂NHR¹¹, NHSO₂N(R¹¹)₂, SO₂NH₂,SO₂NHR¹¹, SO₂N(R¹¹)₂, NHC(O)NH₂, NHC(O)NHR¹¹, NHC(O)N(R¹¹)₂,NR¹¹C(O)N(R¹¹)₂, NO₂, OH, (O), C(O)H, C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F,Cl, Br or I;

wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹³ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁵ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NH₂, C(O)NHR¹⁶,C(O)N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHC(O)OR¹⁶, NR¹⁶C(O)OR¹⁶, OH, F,Cl, Br or I;

wherein each R¹⁶ is R¹⁷ or R^(17A);

R¹⁷ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁸, C(O)OH, NH₂,NHR^(IS) or N(R¹⁸)₂, C(O)R¹⁸, C(O)NH₂, C(O)NHR¹⁸, C(O)N(R¹⁸)₂,NHC(O)R¹⁸, NR¹⁸C(O)R¹⁸, F, Cl, Br or I;

R^(17A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each R¹⁸ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

wherein each of the moieties represented by R¹², R¹³, R¹⁴, R^(17A), andR¹⁸ are independently unsubstituted or substituted with one or two orthree or four of independently selected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, OC(O)R¹⁹, OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹)₂,NHC(O)R¹⁹, NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹, NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹,NR¹⁹C(O)OR¹⁹, NHC(O)NH₂, NHC(O)NHR¹⁹, NHC(O)N(R¹⁹)₂, NR¹⁹C(O)NHR¹⁹,NR¹⁹C(O)N(R¹⁹)₂, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹,C(O)NHSO₂R¹⁹, C(O)NR¹⁹SO₂R¹⁹, SO₂NH₂, SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR¹⁹, C(N)N(R¹⁹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³;

R²⁰ is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²² is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²³ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R²⁴, OR²⁴, SR²⁴,S(O)₂R²⁴, C(O)OH, NH₂, NHR²⁴N(R²⁴)₂, C(O)R²⁴, C(O)NH₂, C(O)NHR²⁴,C(O)N(R²⁴)₂, NHC(O)R²⁴, NR²⁴C(O)R²⁴, NHC(O)OR²⁴, NR²⁴C(O)OR²⁴,NHS(O)₂R²⁴, NR²⁴S(O)₂R²⁴, OH, F, Cl, Br or I;

wherein each R²⁴ is R^(24A) or R^(24B);

R^(24A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl each of which is unfused or fusedwith benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkaneor heterocycloalkene;

R^(24B) is alkyl, alkenyl or alkynyl each of which is unsubstituted orsubstituted with one or two of independently selected R²⁵, OR²⁵, SR²⁵,S(O)₂R²⁵, C(O)OH, NH₂, NHR²⁵N(R²⁵)₂, C(O)R²⁵, C(O)NH₂, C(O)NHR²⁵,C(O)N(R²⁵)₂, NHC(O)R²⁵, NR²⁵C(O)R²⁵, NHC(O)OR²⁵NR²⁵C(O)OR²⁵, OH, F, Cl,Br or I;

wherein each R²⁵ is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl; each of which is unsubstitutedor substituted with NH₂, NH(CH₃), N(CH₃)₂, OH or OCH₃;

wherein each of the moieties represented by R²⁰, R²¹, R²², and R^(24A)are independently unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶, alkenyl, alkynyl, phenyl, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I; and

R²⁶ is alkyl.

Still another embodiment comprises methods for decreasing tumor volumein a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula I

Still another embodiment comprises the use of a compound of Formula Ifor the preparation of a medicament for the treatment of cancer.

Still another embodiment comprises a method of treating leukemia, coloncancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast orcervical carcinomas in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises the use of a compound of Formula Ifor the preparation of a medicament for the treatment of leukemia, coloncancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast orcervical carcinomas.

Still another embodiment comprises methods for potentiation of cytotoxiccancer therapy in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods for potentiation of radiationtherapy in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating ischemiareperfusion injury associated with myocardial infarction, stroke, neuraltrauma or organ transplantation in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formulaI.

Still another embodiment comprises methods of treating reperfusion ofthe eye, kidney, gut or skeletal muscle in a mammal comprisingadministering thereto a therapeutically acceptable amount of a compoundhaving formula I.

Still another embodiment comprises methods of treating arthritis, gout,inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis or uveitis in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formulaI.

Still another embodiment comprises a method of treating rheumatoidarthritis or septic shock in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating diabetes orParkinsons disease in a mammal comprising administering thereto atherapeutically acceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating hypoglycemia in amammal comprising administering thereto a therapeutically acceptableamount of a compound having formula I.

Still another embodiment comprises methods of treating retroviralinfection in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating liver toxicityfollowing acetominophen overdose in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formulaI.

Still another embodiment comprises a method of treating cardiac orkidney toxicities from doxorubicin or platinum based antineoplasticagents in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula I.

Still another embodiment comprises methods of treating skin damagesecondary to sulfur mustards in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound having formulaI.

Still another embodiment comprises the compounds

-   2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoic    acid;-   4-(3-amino-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)amino)-4-oxobutanoic    acid;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   4-(3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(aminomethyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((dimethylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((cyclohexylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((tetrahydro-2H-pyran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((methyl((1-methylpyrrolidin-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((methyl(((2R)-1-methylpyrrolidin-2-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((ispropyamino)methy)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(morpholin-4-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(((2-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((2-ethylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-(morpholin-4-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((4-phenylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-(((2-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((2-methylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-pyrimidin-2-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-pyridin-3-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-pyridin-4-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N,N-diethyl-2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-2-carboxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-piperidin-1-ylpropanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide;-   2-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide.-   3-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-3-carboxamide;-   4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-3-carboxamide;-   N-(2-(isopropylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-morpholin-4-ylacetamide;-   N-(2-morpholin-4-ylethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide;-   4-(3-((2-methylpyrrolidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-azepan-1-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   4-(3-(piperazin-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-azetidin-3-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)N-piperidin-3-ylbenzamide;-   N-(4-(dimethylamino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-methylpiperazin-1-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   4-(3-((4-(isoxazol-5-ylcarbonyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-phenylpiperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(piperidin-2-ylmethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(piperidin-4-ylmethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-piperidin-1-ylethyl)benzamide;-   N-(1-methylazetidin-3-yl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   methyl    4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate;-   N-methyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   4-((2-(methylthio)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-(methylsulfinyl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   methyl    6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate;-   N-ethyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-isopropyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-cyclohexyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-((1-methylpiperidin-2-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-((1-methylpiperidin-4-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-methyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-ethyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-isopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-cyclopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-cyclohexyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   methyl    3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate;-   methyl    5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate;-   4-((5-bromothien-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3-bromothien-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-bromobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(thien-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   methyl    5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-2-carboxylate;-   N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-ethyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide;-   N,N-dimethyl-N′-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)sulfamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-piperidin-1-ylpropanamide;-   4-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)butanamide;-   4-(3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-(2-oxoazetidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-(2-oxoazetidin-1-yl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)benzamide;-   N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)isonicotinamide;-   N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)nicotinamide;-   4-((5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,2′-bipyridin-5-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-2-carboxamide;-   N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)glycinamide.-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-2-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-3-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)methanesulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propane-2-sulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzenesulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyridine-3-sulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)furan-2-sulfonamide;-   1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-imidazole-4-sulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-sulfonamide;-   4-cyano-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzenesulfonamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)naphthalene-1-sulfonamide;-   4-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)benzamide;-   4-((3′-((isopropylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3′-((cyclopentylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3′-((2-methylpyrrolidin-1-yl)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3′-((cyclopropylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((3′-((cyclobutylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-bromo-1-oxidopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((1-oxido-2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   methyl    5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-3-carboxylate;-   4-(3-((4-(24(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;-   1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropanecarboxamide;-   2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropanecarboxamide;-   3-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-L-prolinamide;-   5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-D-prolinamide;-   N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropane-1,1-dicarboxamide;-   2-(benzyloxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-phenylpropanamide;-   3-(2,5-dimethoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-phenylcyclopropanecarboxamide;-   (2S)—N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylbutanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide;-   2-(3-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   2-(2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   2-(4-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   (2R)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylacetamide;-   (2S)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylacetamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-phenoxypropanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-thien-2-ylbutanamide;-   1-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-4-carboxamide;-   2-(3,5-difluorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   N²-acetyl-N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-L-leucinamide;-   N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N²,N²-dipropyl-1-alaninamide;-   4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide;-   N-(2-oxo-2-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylamino)ethyl)benzamide;-   3-(3-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   3-(4-methoxyphenyl)-N-(34((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   2-(3,4-dimethylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   (2R)-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenoxybutanamide;-   4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-thien-2-ylbutanamide;-   2-((4-methylpyrimidin-2-yl)thio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   3-(2-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   3-(4-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylpentanamide;-   2-(4-chloro-2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N′-phenylpentanediamide;-   4-(4-methoxyphenyl)-4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)butanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-diphenylacetamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(phenylsulfonyl)propanamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(3-phenoxyphenyl)acetamide;-   4-ethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   5-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3-fluoro-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2,3-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2,4-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2,5-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3,5-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-propylbenzamide;-   4-isopropyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-isopropoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-(diethylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-butoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-fluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide;-   2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-furamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-furamide;-   2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-furamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-3-carboxamide;-   3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide;-   5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-2-carboxamide;-   1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-2-carboxamide;-   2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-3-carboxamide;-   1,2,5-trimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-3-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-2-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-4-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-5-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isoxazole-5-carboxamide;-   3,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isoxazole-4-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isonicotinamide;-   3-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyridine-2-carboxamide;-   2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide;-   6-hydroxy-N-(3-((4    oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-pyridin-2-ylacetamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-pyridin-3-ylacetamide;-   5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-indole-3-carboxamide;-   5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide;-   6-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2H-chromene-3-carboxamide;-   N³,N³-dimethyl-N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-beta-alaninamide;-   4-(2-(3-bromophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(3-bromo-4-fluorophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2,2,2-trifluoro-1-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-hydroxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3-methoxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3-fluoro-4-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-naphthamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-naphthamide;-   5-chloro-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-tert-butyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-(acetylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-propoxybenzamide;-   1-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-naphthamide;-   2-chloro-5-(methylthio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3,4-diethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)phenyl)benzamide;-   2-benzyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-anilino-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-benzoyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(2-phenylethyl)benzamide;-   5-bromo-2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-(4-methylbenzoyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   2-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   3-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   4-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide;-   N-(2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-3-yl)acetamide;-   4-((6-fluoro-3′-(methylsulfonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-fluoro-4′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-3-carboxamide;-   2′-fluoro-N,N-dimethyl-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1-biphenyl-4-carboxamide;-   4-(3,3,3-trifluoro-2-phenylpropyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(3-bromophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   tert-butyl    2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1-carboxylate;-   4-benzyl 1-tert-butyl    2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1,4-dicarboxylate;-   4-(2-(3-nitrophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(3-aminophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(piperazin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-2-phenoxyacetamide;-   4-(2-(6-fluoro-3′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   methyl    3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoate;-   methyl    3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoate;-   4-(2-(6-fluoro-4′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(6-fluoro-2′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-cyclopropyl-2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   N-(2-(dimethylamino)ethyl)-2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   N-(2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)methanesulfonamide;-   N-(2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide;-   4-(2-(6-fluoro-3′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-cyclopropyl-2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   4-(3-amino-4-chlorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-amino-4-methoxybenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-amino-4-hydroxybenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-amino-4-methylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-(dimethylamino)ethyl)-3′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   3′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   N-(3′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide;-   3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   N-(3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide;-   N-(2-(dimethylamino)ethyl)-3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoic    acid;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione;-   3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;-   4-((4-(phenoxyacetyl)piperazin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(2-(3-bromo-4-fluorophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-4-phenylbutanamide;-   2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide;-   N-(2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide;-   N-((2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)methyl)methanesulfonamide;-   2-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione;-   4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazepan-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-2,6-dione;-   4-(4-fluoro-3-(2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.-   4-(3-(1,1-dioxidoisothiazolidin-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(thien-2-ylmethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(thien-3-ylmethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(pyridin-3-ylmethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(pyridin-4-ylmethyl)benzamide;-   N-(2-(dimethylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(34(dimethylamino)propyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)-N-(3-pyrrolidin-1-ylpropyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(3-piperidin-1-ylpropyl)benzamide;-   N-(3-morpholin-4-ylpropyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(1H-indol-3-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-1,3-thiazol-2-ylbenzamide;-   benzyl    2-oxo-2-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenylamino)ethylcarbamate;-   4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-4-(4-phenoxyphenyl)butanamide;-   benzyl    3-(((3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate;-   2-(4-methylphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)acetamide;-   2-(4-methoxyphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)acetamide;-   4-(4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(3-tert-butyl-2-oxoimidazolidin-1-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-propylphenyl)benzamide;-   N-(2-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-1,1′-biphenyl-4-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-fluoro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-fluoro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)benzamide;-   N-(4-fluoro-2-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-fluoro-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-chloro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-chloro-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-bromo-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-bromo-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-fluoro-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-methoxy-5-(trifluoromethyl)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-hydroxy-6-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-hydroxy-2-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-hydroxy-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)benzamide;-   N-(2-methoxy-5-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-methoxy-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-hydroxy-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-ethoxyphenyl)-((3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(4-propoxyphenyl)benzamide;-   N-(5-tert-butyl-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(5-(acetylamino)-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-2,3-dihydro-1,4-benzodioxin-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)benzamide;-   N-(5-chloro-2,4-dimethoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(3-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(4-piperidin-1-ylphenyl)benzamide;-   N-(4-morpholin-4-ylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-anilinophenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(4-((4-methoxyphenyl)amino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-quinolin-6-ylbenzamide;-   N-(5-hydroxy-1-naphthyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-1H-indazol-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   8-(4-fluorobenzyl)pyrido(2,3-d)pyridazin-5(6H)-one;-   8-(3-chloro-4-fluorobenzyl)pyrido(2,3-d)pyridazin-5(6H)-one;-   (3aR)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazin-1-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N-methylmethanesulfonamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-hydroxy-2-   methylpropanamide;-   (3aS)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazin-1-one;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-phenylethyl)benzamide;-   N-(2-(2-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-2-ylethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-3-ylethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-4-ylethyl)benzamide;-   N-(2-(2-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(1,1′-biphenyl-4-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-(3-(trifluoromethyl)phenyl)ethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl)-N4(2-(4-(trifluoromethyl)phenyl)ethyl)benzamide;-   3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-(4-phenoxyphenyl)ethyl)benzamide;-   N-(2-(3,4-dimethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,4-dimethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,5-dimethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3-ethoxy-4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(4-ethoxy-3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,3-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,4-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,5-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3,4-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3,5-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(1,3-benzodioxol-5-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,3-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(3,4-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(2,6-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,78-hexahydrophthalazin-1-yl)methyl)benzamide;-   (3aS4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-dimethyltetrahydro-4,7-methano(1,3)dioxolo(4,5-c)pyridin-6(3aH)-one;-   4-(1-(3-bromo-4-fluorophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(1-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   8-(3-bromo-4-fluorobenzyl)pyrido(2,3-d)pyridazin-5(6H)-one;-   N-(2-(dimethylamino)ethyl)-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-(2-(diethylamino)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-benzyl-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-benzyl-N-isopropyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-benzyl-N-butyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N,N-dibenzyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-benzyl-N-(2-hydroxyethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-2-ylethyl)benzamide;-   N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide;-   4-(3-((4-hydroxypiperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperidine-3-carboxamide;-   1-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperidine-4-carboxamide;-   4-(3-((4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-methylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-ethylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbaldehyde;-   4-(3-((4-acetylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-phenylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-pyridin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-(2-fluorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-(4-fluorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-(2-chlorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((4-methyl-1,4-diazepan-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(1,1-dioxido-1,2-thiazinan-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)pyrido(2,3-d)pyridazin-5(6H)-one;-   8-(3-chloro-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   4-(1-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(2-oxopyrrolidin-1-yl)acetamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-oxohexanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-methoxypropanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N′-phenylpentanediamide;-   benzyl    2-(dimethylamino)-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylcarbamate;-   8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   4-(3-bromo-4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-((5-oxo-5,6-dihydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   8-(3-amino-4-fluorobenzyl)pyrido(2,3-d)pyridazin-5(6H)-one;-   8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   methyl    2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoate;-   8-(3-amino-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoic    acid;-   N-ethyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   N-cyclobutyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide;-   8-(4-fluoro-3-((4-(morpholin-4-ylcarbonyl)piperazin-1-yl)carbonyl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-N′-phenylpentanediamide;-   1-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-methoxypropanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-5-oxohexanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-phenoxypropanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-4-oxo-4-phenylbutanamide;-   2-(4-(benzyloxy)phenoxy)-N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)acetamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-2-(4-methoxyphenoxy)acetamide.-   N-cyclopropyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   8-(3-((4-(2-ethoxyethyl)piperazin-1-yl)carbonyl)-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-piperidin-1-ylethyl)benzamide;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(3,2-d)pyridazin-8-yl)methyl)-N-(2-oxo-2-(piperidin-1-yl)ethyl)benzamide;-   4-(4-fluoro-3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;    and-   4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-N,N-dimethylpiperazine-1-carboxamide;-   4-(4-fluoro-3-{[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-4-carboxamide;-   4-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide;-   4-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N,N-diethyl-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide;-   8-(3-{[4(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}piperidine-2,6-dione;-   8-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-N,N-dimethylpiperazine-1-carboxamide;-   N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   4-(3-{[4-(3-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-{4-fluoro-3-[(4-methylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(3-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(2-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-3-carboxamide;-   4-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[44(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluoro-3-{[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N,N-diethyl-4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxamide;-   4-{4-fluoro-3-[(4-isopropylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(4-fluoro-3-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-4-carboxamide;-   8-(4-fluoro-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-isopropylurea;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-propylurea;-   N-cyclopentyl-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   N-(2,4-difluorophenyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   N-(tert-butyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   benzyl    4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxylate;-   benzyl    4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate;-   8-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl)-2-morpholin-4-ylpiperazine-1-carbaldehyde;-   8-(4-fluoro-3-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   N,N-diethyl-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxamide;-   8-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-(4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazin-1-yl)-N,N-dimethylacetamide;-   8-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   8-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-piperidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(4-fluoro-3-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   4-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-ethylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   benzyl    (3S)-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-2,5-dioxopyrrolidin-3-ylcarbamate;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-isopropylimidazolidine-2,4-dione;-   (3S)-3-amino-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}pyrrolidine-2,5-dione;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-4-methylpiperazine-1-carboxamide;-   4-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidin-3-yl)-N-methylacetamide;-   N-ethyl-N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidin-3-yl)acetamide;-   8-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-methylimidazolidine-2,4-dione;-   8-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   tert-butyl    3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}tetrahydropyrimidine-1(2H)-carboxylate;-   8-(3-{[3-[3-(dimethylamino)propyl]tetrahydropyrimidin-1(2H)-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   5-benzyl-3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}imidazolidine-2,4-dione;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione;-   8-{4-fluoro-3-[(3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{3-[(4-benzoylpiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(3-chlorobenzoyl)piperidin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   benzyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate;-   tert-butyl    (3R)-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-3-phenylpiperazine-1-carboxylate;-   8-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methyl-N-phenylurea;-   N-ethyl-N-(1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}pyrrolidin-3-yl)acetamide;-   4-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]glycine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]leucine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]alanine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]phenylalanine;-   3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;-   8-(4-fluoro-3-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(3-{[4-(cyclopropylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methylcyclopropyl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-4-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-(4-fluoro-3-{[(2R)-2-phenylpiperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(cyclopentylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(5-chloropyridin-2-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-{[1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(6-chloro-5-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-6-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   benzyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate;-   8-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   ethyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate;-   8-{3-[(2,2-dimethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   5-benzyl-3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;-   4-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(5-oxopyrrolidin-2-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-{[(4R)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl}piperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-(methylamino)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   8-{4-fluoro-3-[(4-isonicotinoyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-6-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-fluorobenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-furoyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   tert-butyl    4-[{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}(methyl)amino]piperidine-1-carboxylate;-   tert-butyl    4-({2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}amino)piperidine-1-carboxylate;-   tert-butyl    1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-ylcarbamate;-   8-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide;-   8-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-(4-hydroxycyclohexyl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide;-   tert-butyl 2-(ethyl    {2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethylcarbamate;-   2-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   N-[1-(1H-benzimidazol-5-ylcarbonyl)piperidin-4-yl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide;-   2-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   N-(2-aminoethyl)-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   4-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide;-   4-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[3-({4-[(5-chloro-6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide;-   4-{4-fluoro-3-[(4-{[1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   4-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide;-   4-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   4-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   4-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   4-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[(1S,2S)-2-aminocyclohexyl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide.-   N-[2-(benzoylamino)ethyl]-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl]benzamide;-   N-[2-(ethyl    {2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthialazin-1-yl)methyl]benzoyl}amino)ethyl]pyrrolidine-1-carboxamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-(1-pyridin-2-ylpiperidin-4-yl)benzamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)pyridine-2-carboxamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)nicotinamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)isonicotinamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-indazole-6-carboxamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-2-furamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1,3-thiazole-4-carboxamide;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methylcyclobutanecarboxamide;-   4-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-pyrazole-4-carboxamide;-   4-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N-{2-[(2,6-difluorobenzoyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N-[2-(ethyl    {2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethyl]nicotinamide;    and therapeutically acceptable salts, prodrugs, esters, amides,    salts of prodrugs, salts of esters and salts of amides thereof.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties of compounds herein are represented by identifiers(capital letters with numerical and/or alphabetical superscripts) andmay be specifically embodied.

It is meant to be understood that proper valences are maintained for allcombinations herein, that monovalent moieties having more than one atomare attached through their left ends.

It is also meant to be understood that a specific embodiment of avariable moiety may be the same or different as another specificembodiment having the same identifier.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

BOC is Di-tert-butyl dicarbonate

C-18 is dimethyl-octadecylsilane

DCI for chemical ionization for direct introduction,

DME for 1,2-dimethoxyethane,

DMSO for dimethylsulfoxide,

ESI for electrospray ionization,

HATU for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,

HPLC for high performance liquid chromatography,

MS for mass spectrometry,

TFA for trifluoroacetic acid,

As used in reference to ¹H NMR, the symbol “δ” refers to a ¹H NMRchemical shift.

As used in reference to ¹H NMR, the abbreviation “br” refers to a broad¹H NMR signal.

As used in reference to ¹H NMR, the abbreviation “d” refers to a doublet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “dd” refers to adoublet of doublets ¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “m” refers to amultiplet ¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “q” refers to a quartet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “s” refers to a singlet¹H NMR peak.

As used in reference to ¹H NMR, the abbreviation “t” refers to a triplet¹H NMR peak.

The term “alkenyl,” as used herein, means monovalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon double bonds, such as C₂-alkenyl, C₃-alkenyl, C₄-alkenyl,C₅-alkenyl, C₆-alkenyl and the like.

The term “alkyl,” as used herein, means monovalent, saturated, straightor branched chain hydrocarbon moieties, such as C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl and the like.

The term “alkynyl,” as used herein, means monovalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon triple bonds, such as C₂-alkynyl, C₃-alkynyl, C₄-alkynyl,C₅-alkynyl, C₆-alkynyl and the like.

The term “cycloalkane,” as used herein, means saturated cyclic orbicyclic hydrocarbon moieties, such as C₄-cycloalkane, C₅-cycloalkane,C₆-cycloalkane, C₇-cycloalkane, C₈-cycloalkane, C₉-cycloalkane,C₁₀-cycloalkane, C₁₁-cycloalkane, C₁₂-cycloalkane and the like.

The term “cycloalkyl,” as used herein, means monovalent, saturatedcyclic and bicyclic hydrocarbon moieties, such as C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₇-cycloalkyl,C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl, C₁₁-cycloalkyl,C₁₂-cycloalkyl and the like.

The term “cycloalkene,” as used herein, means cyclic and bicyclichydrocarbon moieties having one or more than one carbon-carbon doublebonds, such as C₅-cycloalkene, C₆-cycloalkene, C₇-cycloalkene,C₈-cycloalkene, C₉-cycloalkene, C₁₀-cycloalkene, C₁₁-cycloalkene,C₁₂-cycloalkene and the like.

The term “cycloalkenyl,” as used herein, means monovalent, cyclichydrocarbon moieties having one or more than one carbon-carbon doublebonds, such as C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl,C₁₁-cycloalkenyl, C₁₂-cycloalkenyl and the like.

The term “heteroarene,” as used herein, means furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole,1,3,4-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, thiophene, triazineand 1,2,3-triazole.

The term “heteroaryl,” as used herein, means furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,1,2,3-thiadiazoyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl,triazinyl and 1,2,3-triazolyl.

The term “heterocycloalkane,” as used herein, means cycloalkane havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkane having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “heterocycloalkene,” as used herein, means cycloalkene havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkene having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “heterocycloalkyl,” as used herein, means cycloalkyl having oneor two or three CH₂ moieties replaced with independently selected O, S,S(O), SO₂ or NH and one or two CH moieties unreplaced or replaced with Nand also means cycloalkyl having one or two or three CH₂ moietiesunreplaced or replaced with independently selected O, S, S(O), SO₂ or NHand one or two CH moieties replaced with N.

The term “heterocycloalkenyl,” as used herein, means cycloalkenyl havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkenyl having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “cyclic moiety,” as used herein, means benzene, cycloalkane,cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl,heterocycloalkane, heterocycloalkyl, heterocycloalkene,heterocycloalkenyl and phenyl.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, wherein the terms “R” and “S”are as defined in Pure Appl. Chem. (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon atoms with equal amounts of R and Sconfigurations are racemic at those atoms. Atoms having excess of oneconfiguration over the other are assigned the configuration in excess,preferably an excess of about 85%-90%, more preferably an excess ofabout 95%-99%, and still more preferably an excess greater than about99%. Accordingly, this invention is meant to embrace racemic mixtures,relative and absolute diastereoisomers and the compounds thereof.

Compounds of this invention may also contain carbon-carbon double bondsor carbon-nitrogen double bonds in the Z or E configuration, in whichthe term “Z” represents the larger two substituents on the same side ofa carbon-carbon or carbon-nitrogen double bond and the term “E”represents the larger two substituents on opposite sides of acarbon-carbon or carbon-nitrogen double bond. The compounds of thisinvention may also exist as a mixture of “Z” and “E” isomers.

Compounds of this invention containing NH, C(O)H, C(O)OH, C(O)NH₂, OH orSH moieties may have attached thereto prodrug-forming moieties. Theprodrug-forming moieties are removed by metabolic processes and releasethe compounds having the freed NH, C(O)H, C(O)OH, C(O)NH₂, OH or SH invivo. Prodrugs are useful for adjusting such pharmacokinetic propertiesof the compounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Metabolites of compounds having Formula I, produced by in vitro or invivo metabolic processes, may also have utility for treating diseasescaused or exacerbated by unregulated or overexpressedpoly(ADP-ribose)polymerase.

Certain precursor compounds of compounds having Formula I may bemetabolized in vitro or in vivo to form compounds having Formula I andmay thereby also have utility for treating diseases caused orexacerbated by unregulared or overexpressed poly(ADP-ribose)polymerase.

Compounds having Formula I may exist as acid addition salts, basicaddition salts or zwitterions. Salts of compounds having Formula I areprepared during their isolation or following their purification. Acidaddition salts are those derived from the reaction of a compound havingFormula I with acid. Accordingly, salts including the acetate, adipate,alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, formate, fumarate, glycerophosphate, glutamate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, phosphate, picrate, propionate, succinate,tartrate, thiocyanate, trichloroacetic, trifluoroacetic,para-toluenesulfonate and undecanoate salts of the compounds havingFormula I are meant to be embraced by this invention. Basic additionsalts of compounds are those derived from the reaction of the compoundshaving Formula I with the bicarbonate, carbonate, hydroxide, orphosphate of cations such as lithium, sodium, potassium, calcium andmagnesium.

Compounds having Formula I may be administered, for example, bucally,ophthalmically, orally, osmotically, parenterally (intramuscularly,intraperintoneally intrasternally, intravenously, subcutaneously),rectally, topically, transdermally and vaginally.

Therapeutically effective amounts of a compound having Formula I dependon recipient of treatment, disease treated and severity thereof,composition comprising it, time of administration, route ofadministration, duration of treatment, potency, rate of clearance andwhether or not another drug is co-administered. The amount of a compoundhaving Formula I used to make a composition to be administered daily toa patient in a single dose or in divided doses is from about 0.001 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula I may be administered with or without anexcipient.

Excipients include, for example, encapsulators and additives such asabsorption accelerators, antioxidants, binders, buffers, coating agents,coloring agents, diluents, disintegrating agents, emulsifiers,extenders, fillers, flavoring agents, humectants, lubricants, perfumes,preservatives, propellants, releasing agents, sterilizing agents,sweeteners, solubilizers, wetting agents and mixtures thereof.

Compounds having Formula I may be radiolabeled with a radioactiveisotope such as carbon (i.e. ¹³C), hydrogen (i.e. ³H), nitrogen (i.e.¹⁵N), phosphorus (i.e. ³²P), sulfur (i.e. ³⁵S), iodide (i.e. ¹²⁵I) andthe like. Radioactive isotopes may be incorporated into the compoundshaving Formula I by reacting the same and a radioactive derivitizingagent or by incorporating a radiolabeled intermediate into theirsyntheses. The radiolabeled compounds of Formula I are useful for bothprognostic and diagnostic applications and for in vivo and in vitroimaging.

Compounds having Formula I may be incorporated into devices such as, butnot limited to, arterio-venous grafts, billiary stents, by-pass grafts,catheters, central nervous system shunts, coronary stents, drug deliveryballoons, peripheral stents and ureteural stents, each of which may beused in areas such as, but not limited to, the vasculature forintroduction of a compound having Formula I into selected tissues ororgans in the body. One measure of the effectiveness of compounds havingFormula I is reduction or elimination of device-associated thrombi andcomplications associated therewith.

Compounds having Formula I can used as a radiosensitizers which enhancethe efficacy of radiotherapy. Examples of radiotherapy include, but arenot limited to, external beam radiotherapy, teletherapy, brachtherapyand sealed and unsealed source radiotherapy.

Excipients for preparation of compositions comprising a compound havingFormula I to be administered orally include, for example, agar, alginicacid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyleneglycol, carbomers, castor oil, cellulose, cellulose acetate, cocoabutter, corn starch, corn oil, cottonseed oil, cross-povidone,diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate,fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil,hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose,magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides,olive oil, peanut oil, potassium phosphate salts, potato starch,povidone, propylene glycol, Ringer's solution, safflower oil, sesameoil, sodium carboxymethyl cellulose, sodium phosphate salts, sodiumlauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearylfumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfurylalcohol, triglycerides, water and mixtures thereof. Excipients forpreparation of compositions comprising a compound having Formula I to beadministered ophthalmically or orally include, for example, 1,3-butyleneglycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid estersof sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil,polyethylene glycols, propylene glycol, sesame oil, water and mixturesthereof. Excipients for preparation of compositions comprising acompound having Formula I to be administered osmotically include, forexample, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound havingFormula I to be administered parenterally include, for example,1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germoil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound havingFormula I to be administered rectally or vaginally include, for example,cocoa butter, polyethylene glycol, wax and mixtures thereof.

Compounds having formula I are also expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, aurora kinase inhibitors, Bcr-Ablkinase inhibitors, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemiaviral oncogene homolog (ErbB2) receptor inhibitors, growth factorinhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase(HDAC) inhibitors inhibitors, hormonal therapies, immunologicals,intercalating antibiotics, kinase inhibitors, mammalian target ofrapomycin inhibitors, mitogen-activated extracellular signal-regulatedkinase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's),platinum chemotherapeutics, polo-like kinase inhibitors, proteasomeinhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinaseinhibitors, retinoids/deltoids plant alkaloids, topoisomerase inhibitorsand the like.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, Cloretazine™ (VNP 40101M), cyclophosphamide, decarbazine,estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine(CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine,nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa,treosulfan, trofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and thelike.

Bcr-Abl kinase inhibitors include DASATINIBx (BMS-354825). GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),Herceptin® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®,NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam) ibuprofin cream, ALEVE® andNAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin),CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL®(ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen(pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034),(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap,vatalanib, ZACTIMA™ (vandetanib, ZD-6474) and the like.

Antimetabolites include ALIMTA® (premetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR,enocitabine, ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil(5-FU) alone or in combination with leucovorin, GEMZAR® (gemcitabine),hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurineriboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed,ocfosate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine,trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and thelike.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (doxorubicin), elsamitrucin, epirbucin,glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), fadrozole,FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®, (letrozole),formestane, glucocorticoids, HECTOROL® or RENAGEL® (doxercalciferol),lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX®(mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate),PLENAXIS™ (abarelix), predisone, PROPECIA® (finasteride), rilostane,SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone(LHRH)), vantas, VETORYL®, (trilostane or modrastane), ZOLADEX®(fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH 1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG 132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b), or interferon gamma-n 1,combinations thereof and the like. Other agents include ALFAFERONE®,BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab,molgramostim, MY LOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFG1),PROVENGE®, sargaramostim, sizofilan, teceleukin, TheraCys®, ubenimex,VIRULIZIN®, Z-100, WF-10, PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C), cytosine arabinoside,doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil),floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™(triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like.

Compounds of the present invention are also intended to be used as aradiosensitizer that enhances the efficacy of radiotherapy. Examples ofradiotherapy include, but are not limited to, external beamradiotherapy, teletherapy, brachtherapy and sealed and unsealed sourceradiotherapy.

Additionally, compounds having formula I may be combined with otherchemptherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN®, ALTOCOR® or MEVACOR® (lovastatin),AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN™ (exisulind),AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotne), AVE-8062,BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor),canvaxin (vaccine), CeaVac™ (cancer vaccine), CELEUK® (celmoleukin),CEPLENE® (histamine dihydrochloride), CERVARIX™ (human papillomavirusvaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CyPat™,combrestatin A4P, DAB(389)EGF or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906, GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16,18) recombinant vaccine), gastrimmune, genasense, GMK (gangliosideconjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone,histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38,IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin,interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafamib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), OncoVAX (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OvaRex® MAb(murine monoclonal antibody), paditaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), Taxoprexin®(DHA-paclitaxel), TELCYTA™ (TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFerade™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY® (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa(zolendronic acid), zorubicin and the like.

In one embodiment, compounds having Formula I are used in a method oftreating cancer in a mammal comprising administering thereto atherapeutically acceptable amount of a compound of claim 1 incombination with a chemotherapeutic agent selected from temozolomide,dacarbazine, cyclophosphamide, carmustine, melphalan, lomustine,carboplatin, cisplatin, 5-FU+/−leucovorin, gemcitabine, methotrexate,bleomycin, irinotecan, camptothecin, or topotecan.

It is expected that compounds having formula I would also inhibit growthof cells derived from a pediatric cancer or neoplasm including embryonalrhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatricacute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma,pediatric anaplastic ependymoma, pediatric anaplastic large celllymphoma, pediatric anaplastic medulloblastoma, pediatric atypicalteratoid/rhabdoid tumor of the central nervous system, pediatricbiphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatriccancers of Ewing's family of tumors such as primitive neuroectodermalrumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorablehistology Wilm's tumor, pediatric glioblastoma, pediatricmedulloblastoma, pediatric neuroblastoma, pediatricneuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers(such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidneytumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such aslymphoma and skin cancer and the like (commonly-owned U.S. applicationSer. No. 10/988,338), Cancer Res., 2000, 60, 6101-10); and autoimmunedisorders include, acquired immunodeficiency disease syndrome,autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatorydiseases, thrombocytopenia and the like (Current Allergy and AsthmaReports 2003, 3:378-384; Br. J. Haematol. 2000 September; 110(3):584-90; Blood 2000 Feb. 15; 95(4):1283-92; and New England Journal ofMedicine 2004 September; 351(14): 1409-1418).

PARP Enzyme Inhibition Assay

Nicotinamide[2,5′,8-3H]adenine dinucleotide and strepavidin SPA beadswere purchased from Amersham Biosiences. Recombinant HumanPoly(ADP-Ribose) Polymerase (PARP), purified from E. coli and6-Biotin-17-NAD⁺, were purchase from Trevigen. NAD⁺, histone,aminobenzamide, 3-amino benzamide and Calf Thymus DNA (dcDNA) werepurchased from Sigma. Stem loop oligonucleotide containing MCAT sequencewas obtained from Qiagen. The oligos were dissolved to 1 mM in annealingbuffer containing 10 mM Tris HCl pH 7.5, 1 mM EDTA, and 50 mM NaCl,incubated for 5 minutes at 95° C., and annealed at 45° C. for 45minutes. Histone H1 (95% electrophoretically pure) was purchased fromRoche. Biotinylated histone H1 was prepared by treating the protein withSulfo-NHS-LC-Biotin from Pierce. The biotinylation reaction wasconducted by slowly and intermittently adding 3 equivalents of 10 mMSulfo-NHS-LC-Biotin to 100 μM Histone H1 in phosphate-buffered saline,pH 7.5, at 4° C. with gentle vortexing over 1 minute followed bysubsequent 4° C. incubation for 1 hour. Streptavidin coated (FlashPlatePlus) microplates were purchased from Perkin Elmer.

PARP1 assay was conducted in PARP assay buffer containing 50 mM Tris pH8.0, 1 mM DTT, 4 mM MgCl₂. PARP reactions contained 1.5 μM [³H]-NAD⁺(1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM sIDNA, and 1 nMPARP enzyme. Auto reactions utilizing SPA bead-based detection werecarried out in 100 μL volumes in white 96 well plates. Reactions wereinitiated by adding 50 μl of 2×NAD⁺ substrate mixture to 50 μL of 2×enzyme mixture containing PARP and DNA. These reactions were terminatedby the addition of 150 μL of 1.5 mM benzamide (˜1000-fold over itsIC₅₀). 170 μL of the stopped reaction mixtures were transferred tostreptavidin Flash Plates, incubated for 1 hour, and counted using aTopCount microplate scintillation counter. The EC_(50s) for exemplifiedcompounds of this invention are provided in Table 1.

Cellular PARP Assay:

C41 cells were treated with a compound of this invention for 30 minutesin 96 well plate. PARP was then activated by damaging DNA with 1 mM H₂O₂for 10 minutes. The cells were then washed with ice-cold PBS once andfixed with pre-chilled methanol:acetone (7:3) at −20° C. for 10 minutes.After air-drying, the plates were rehydrated with PBS and blocked 5%non-fat dry milk in PBS-TWEEN20® (Sigma, St. Louis, Mo.) (0.05%)(blocking solution) for 30 minutes at room temperature. The cells wereincubated with anti-PAR antibody 10H (1:50) in Blocking solution at 37°C. for 60 minutes followed by washing with PBS— TWEEN20® 5 times, andincubation with goat anti-mouse fluorescein 5(6)-isothiocyanate-coupledantibody (1:50) and 1 μg/ml 4′,6-diamidino-2-phenylindole (DAPI) inblocking solution at 37° C. for 60 minutes. After washing withPBS-TWEEN20® 5 times, the analysis was performed using an FMAXFLUORESCENCE MICROPLATE READER® (Molecular Devices, Sunnyvalle, Calif.),set at the excitation wavelength of 490 nm and emission wavelength of528 nm fluorescein 5(6)-isothiocyanate (FITC) or the excitationwavelength of 355 nm and emission wavelength of 460 nm (DAPI). The PARPactivity (FITC signal) was normalized with cell numbers (DAPI).

The cellular assay measures the formation of poly ADP-ribose by PARPwithin cells and demonstrates that compounds of this invention penetratecell membranes and inhibit PARP in intact cells. Due to variability inthe cellular assay,2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide was run as acomparator in each assay and data reported as the ratio of test compoundEC₅₀ relative to the EC₅₀ of2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide obtained inthat particular assay. The mean EC₅₀ of2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide for all assayscarried out was 0.0032 μM (n=270) and generally ranged from 0.001 to0.013 μM. (ratio EC₅₀=EC₅₀ test compound/EC50 comparator compound). TheEC₅₀ data (nM) are shown in TABLE 1.

TABLE 1 Inhibition of PARP by Compounds Having Formula I PARP-1 Cell,Ratio Example (K_(i), nM) EC₅₀, nM 1 91 2 44 3 3 >300 4 1.5 0.5 5 1.1 176 108 7 534 8 862 9 319 10 411 11 1489 12 963 13 225 14 173 15 390 16307 17 283 18 83 19 75 278 20 480 21 148 22 372 23 562 24 794 25 1610 261720 27 2110 28 682 29 516 30 766 31 700 32 1960 33 347 34 1030 35 182036 2130 37 673 38 6 75 39 48 >300 40 23 >300 41 1010 42 20 13 43 8 2.344 2 13 45 14 >300 46 42 47 1.2 1.2 48 0.7 49 49 20 59 50 19 >300 51 4752 13 15 53 10 15 54 205 55 1 15 56 5 >300 57 60 58 51 373 59 24 69 60 36.9 61 6 12 62 42 63 23 >1000 64 40 11 65 82 66 87 >1000 67 50 700 68351 69 40 43 70 101 71 639 72 144 73 86 74 102 75 56 >1000 76 473 77 19578 165 79 18 121 80 47 570 81 123 82 691 83 126 84 617 85 396 86 390 8756 88 96 89 111 90 68 91 70 92 167 93 840 94 856 95 1260 96 2610 97 39098 286 99 44 179 100 39 110 101 21 162 102 26 148 103 1050 104 1230 105725 106 290 107 216 108 576 109 609 110 372 111 12 61 112 136 113 6 662114 65 286 115 157 116 578 117 477 118 2030 119 703 120 626 121 776 122644 123 121 125 47 798 126 286 127 14 13 128 43 129 41 53 130 24 57 13132 132 1040 133 724 134 133 135 16 136 76 137 69 138 22 62 139 206 14060 141 77 142 11 41 143 78 144 125 145 57 146 678 147 41 148 74 149 22262 150 16 140 151 531 152 741 153 6 95 154 56 155 126 156 25 157 124158 1590 159 4 30 160 11 40 161 64 162 51 163 35 164 28 98 165 14 244166 5 40 167 56 168 127 169 99 170 1700 171 56 172 3 5 173 2 32 174 655175 21 215

PARP-1 Cell, Ratio Example (K_(i), nM) EC₅₀, nM 176 43 177 156 178 462179 238 180 159 181 212 182 292 183 166 184 154 185 250 186 160 187 1250188 185 189 175 190 263 191 31 143 192 43 193 100 194 61 195 177 196 286197 146 198 403 199 196 200 158 201 570 202 93 203 103 204 203 205 176206 18 212 208 22 423 209 395 210 211 98 212 65 213 82 214 7 238 215 85216 82 217 5 44 218 86 219 9 38 220 14 137 221 1540 222 248 223 206 2249220 225 41 226 40 >1000 227 60 228 98 229 49 230 96 231 110 23212 >1000 233 158 234 57 235 198 236 4 >1000 237 68 238 47 239 554 240285 241 1450 242 610 243 92 244 2340 245 963 246 52 247 48 248 2 43 24985 250 210 251 446 252 19 >1000 253 229 254 4120 255 335 256 346 2572280 258 1770 259 91 260 243 261 556 262 304 263 144 264 662 26558 >1000 266 19 >1000 267 534 268 638 269 1050 270 487 271 1140 272 204273 257 274 222 275 471 276 943 277 436 278 185 279 467 280 303 281 309282 1710 283 442 284 2210 285 150 286 58 >1000 287 771 288 431 289 0.716 290 1 6 291 0.7 0.2 292 116 293 338 294 204 295 912 296 683 297 1440298 2 2.7 299 4 5.5 300 2 1.2 301 6 26 302 2 2.6 303 0.8 0.4 304 17 26305 3 4 306 6 23 307 2 4 308 30 309 29 310 26 311 58 312 131 313 95 31432 315 23 10 316 34 317 25 39 318 28 319 94 320 165 321 223 322 556 323237 324 131 325 5 36 326 70 327 1630 328 7 48 329 789 330 99 331 140 332635 333 892 334 191 335 122 336 363 337 124 338 136 339 120 340 279 341154 342 134 343 87 344 194 345 149 346 33 158 347 337 348 259 349 55 350143 351 277 352 154 353 59 354 363 355 92 356 180 357 402 358 66 359 151360 94 361 76 362 185 363 132 364 316 365 120 366 23 105 367 45 368 56369 4210 370 4310 371 14 51 372 1570 373 22 211 374 27 375 51 376 173377 42 378 28 379 20 173 380 71 381 67 382 79 383 44 384 40 385 42 38633 387 44 388 88 389 48 390 31 391 44 392 30 393 70 394 22 395 38 396 83397 50 398 82 399 65 400 22 401 48 402 86 403 56 404 55 405 19 135 40642 407 22 659 408 69 409 33 410 242 411 8 4.6 412 324 413 18 51 414 119415 3200 418 34 419 16 2.1 420 21 421 68 422 105 423 120 424 31 426 1428 427 22 132 428 5 14 429 19 430 5 226 434 6 6.3 435 20 13 436 10 1.8437 4 438 3 6.4 439 8 9.4 440 3 3.4 441 3 2 442 0.8 0.9 443 16 14 444 4445 6 2.3 446 10 16 447 10 4 448 694 449 103 450 122 451 56 452 2 2.5453 14 454 16 455 1.3 0.9 456 5 14 457 0.7 0.2 458 2490 459 3 7 460 580461 404 462 163 463 1880 464 5 3.1 465 3.5 13 467 116 468 249 470 18 10471 51 472 9 25 473 2 106 474 1.4 4 475 1.4 13 476 12 30 477 4 6 478 215 479 1.3 3.5 481 12 33 483 5 16 484 14 18 485 14 53 486 15 9.6 487 1041 490 0.7 0.7 491 191 492 1.6 0.35 494 0.9 0.6 495 1.9 0.4 496 0.8 0.3497 1.1 0.8 498 2.7 25 499 1.6 2 500 3 28 501 4 3 502 1.5 0.6 503 1.3 2504 3.6 0.7 505 6 17 506 1.4 4.4 507 0.8 1.2 508 7 509 3 27 510 1.2 8511 0.4 0.7 512 1.3 10 513 6 10 514 9 18 515 3 0.9 516 6 6 517 5 6 51810 519 5 166 520 0.1 2.3 522 1.9 0.4 523 13 0.4 524 5 2.7 525 1.6 0.2526 4 2 527 3 1.3 528 4 0.8 529 2 0.4 530 2 0.6 531 2 0.5 532 4 71 533 21 534 2 110 535 4 536 0.5 0.2 537 2.5 3.4 538 374 539 191 540 204 541 71542 548 543 5 5 544 4 545 1 0.3 546 1.2 0.3 547 2.3 0.8 548 2 0.4 549 10.2 550 1.1 0.7 551 0.9 2.3 553 0.8 3 554 2.1 2.3 555 0.8 556 0.8 29 5571.1 3 559 1.4 35 560 2 149 561 3 1.7 562 0.9 3.4 563 3.5 58 564 2.5 1.5565 1.4 9 566 4 6 567 0.9 10 568 1.1 0.8 569 1.2 8 570 8 114 571 4 5 5723 22 573 0.9 3 574 1.3 4 575 2 0.6 576 0.9 0.3 577 3 3 578 1.1 0.6 579 10.25 580 1.8 0.4 581 0.5 5 582 65 583 2.3 7 584 68 585 1.3 0.4 586 1.10.7 587 1 0.3 590 1.9 0.7 591 0.5 1 593 1.3 2.5 594 0.7 2 595 6 43 596 635 597 0.8 3.6 598 9 54 599 1.1 0.4 600 0.7 2 601 1.1 1.7 602 3 0.8 6038 604 15 605 32 606 17 607 0.9 38 609 1.8 1.1 610 1.7 0.4 611 1.6 6 6123 1.6 613 1.8 0.5 614 25 616 2.3 10 617 1.9 618 41 619 4 2.6 620 2.2 8621 8 2.4 622 2.4 0.7 623 3 0.9 624 2.5 0.2 625 21 626 173 627 85 628 54630 0.7 1 631 2.8 3.5 632 0.9 1.2 633 0.6 0.9 634 1.9 1.4 635 1.8 0.8636 1.8 10 637 4 16 638 7 6 639 3 55 640 0.7 2.4 641 1.3 45 643 1.2 72644 3 114 645 1.5 47 646 0.7 13 647 1.7 18 649 0.6 651 1.1 0.4 654 1.2655 0.7 657 0.8 10 658 1 17 659 2.5 5 660 1.4 36 661 1.5 37 662 1.5 17663 1 100 664 1.3 665 1.1 13 666 1.5 0.8 667 20 668 1.9 2.4 669 1.2 0.2672 84 673 1 2 674 1.1 0.6 675 1.2 34 677 1.5 0.8 678 1.1 1.1 679 1.40.6 680 1.1 681 40 682 2.4 106 683 2.6 125 684 2.8 22 685 2.2 686 1.9687 4.2 6 688 2.4 9 689 2.7 690 2.4 18 691 2.1 0.7 692 1.6 11 693 2 34694 1.7 11 695 1 1.7 696 2.5 697 2.2 56 698 11 699 74 700 2.8 3 701 2.3702 2.1 703 2.3 704 0.6 23 705 1.4 9 706 5 707 32 708 1.7 709 53 710 7711 3 9 712 4 713 1.8 714 0.8 1 715 4 716 5 717 4 718 2.6 719 7 9 7201.4 1.6 721 3 64 722 1.2 1 723 1.3 19 724 7 725 5 8 726 4 15 727 1.4 0.7728 1.8 2.1 729 48 730 1.3 0.6 731 11 49 733 1.7 2.3 734 9 58 735 1.5 25736 4 76 738 14 739 1.3 2 740 52 742 1.8 3 743 2.7 6 745 8 10 746 1.5 4747 1.5 748 1 749 1.4 750 1.1 13 751 1.5 5 753 92 754 0.6 17 755 1.5 0.5756 0.9 0.4 757 1.2 1.6 758 1.4 759 0.3 1.3 761 0.6 1.4 762 1 7 763 12.4

Selected compounds of Formula I wherein A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ is C₁-alkylwere run in the PARP Enzyme Inhihition Assay and the PARP Cellular Assaydescribed above. Compounds outside of Formula I wherein at the positionof A² is instead a bond also were run in the PARP Enzyme InhihitionAssay and the PARP Cellular Assay described above. The results of theassays are described in TABLE 2, below:

TABLE 2 PARP Cell PARP Cell A² is R⁵, wherein R⁵ is −1 (Ki, Ratio −1(Ki, Ratio C₁-alkyl nM) EC₅₀ No A² nM) EC₅₀

6   16.4 

291

1.2  0.85

191Selected compounds of Formula I wherein A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ is C₁-alkylwherein R⁵ is substituted with R¹⁰, wherein R¹⁰ is phenyl, either with apara-substituted F, as shown in Formula (Is):

or without a para-substituted F were run in the PARP Enzyme InhihitionAssay and the PARP Cellular Assay described above. Results are shown inTable 3.

TABLE 3 PARP-1 Cell EC₅₀ PARP-1 Cell EC₅₀ H analogs (K_(i), nM) ratio Fanalogs (K_(i), nM) ratio

12 22.5

2.9 5.8

6.3 246

0.7 34.4

1.9 20.9

0.7 2.6

39.6 40.9

1.2 0.85

2 1.7

1.1 0.19

3.2 3.2

0.6 0.34

9 14.1

15.8 17.6

280 —

18.4 5.6

0.8 0.93

0.7 0.3

3 6.1

0.1 2.3

10 1.8

1.8 0.4

3 1.9

2 0.4

3 3.2

3 0.9

10 15

5 6

4 —

13 1.3

6 2.2

4 0.8

10 3.8

1.5 0.6

19 —

3 28

5 13

1.3 2

5 215

2.7 25

27 —

6 17

13 3

3.6 0.7

24 31

1.1 0.6

As PARP inhibitors, the compounds of this invention have numeroustherapeutic applications related to ischemia reperfusion injury,inflammatory diseases, degenerative diseases, protection from adverseeffects of cytotoxic compounds, and potentiation of cytotoxic cancertherapy. In particular, compounds of this invention potentiate radiationand chemotherapy by increasing cell death of cancer cells, limitingtumor growth, decreasing metastasis, and prolonging the survival oftumor-bearing mammals. Compounds having formula I can treat leukemia,colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of thebreast, and cervical carcinomas.

Other therapeutic applications include retroviral infection, arthritis,gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, uveitis, diabetes, Parkinsons disease, myocardialinfarction, stroke, other neural trauma, organ transplantation,reperfusion of the eye, reperfusion of the kidney, reperfusion of thegut, reperfusion of skeletal muscle, liver toxicity followingacetominophen overdose, cardiac and kidney toxicities from doxorubicinand platinum based antineoplastic agents, and skin damage secondary tosulfur mustards. (G. Chen et al. Cancer Chemo. Pharmacol. 22 (1988),303; C. Thiemermann et al., Proc. Natl. Acad. Sci. USA 94 (1997),679-683 D. Weltin et al. Int. J. Immunopharmacol. 17 (1995), 265-271; H.Kriger et al. Inflammation 20 (1996), 203-215; W. Ehrlich et al.Rheumatol. Int. 15 (1995), 171-172; C. Szabo et al., Proc. Natl. Acad.Sci. USA 95 (1998), 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol.342 (1998), 67-76; V. Burkhart et al., Nature Medicine (1999), 5314-19).

Compounds of Formula I

In one embodiment of formula I

or a salt thereof, wherein

A¹ is R¹ or R², wherein A¹ is unsubstituted or substituted with one ortwo OH, CN, C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl,cycloalkane, OR^(A) or NR^(A)R^(A);

R^(A) is H or alkyl;

R¹ is cycloalkane or cycloalkene each of which is unfused or fused withR^(1A);

R^(1A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R² is heterocycloalkane or heterocycloalkene; each of which is unfusedor fused with R^(2A);

R^(2A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

A² is OR⁴, NHR⁴, N(R⁴)₂, SR⁴, S(O)R⁴, SO₂R⁴ or R⁵;

wherein each R⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl; each of which issubstituted with R¹⁰;

R⁵ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl or C₅-alkyl; each of whichis substituted with R¹⁰, and further unsubstituted or substituted withone or two or three of independently selected OR¹⁰, NHR¹⁰, N(R¹⁰)₂,SR¹⁰, S(O)R¹⁰, SO₂R¹⁰ or CF₃;

wherein each R¹⁰ is R^(10A), R^(10B) or R^(10C); each of which must beattached at a carbon atom;

R^(10A) is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R^(10B) is

each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which are unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R^(10C) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl; each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein each R¹⁰ is independently unsubstituted or substituted with oneor two or three of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹,SO₂R¹¹, NH₂, NHR¹¹, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NR¹¹C(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹,NR¹¹C(O)OR¹¹, NHSO₂NH₂, NHSO₂NHR¹¹, NHSO₂N(R¹¹)₂, SO₂NH₂, SO₂NHR¹¹,SO₂N(R¹¹)₂, NHC(O)NH₂, NHC(O)NHR¹¹, NHC(O)N(R¹¹)₂, NR¹¹C(O)N(R¹¹)₂, NO₂,OH, (O), C(O)H, C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I;

wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹³ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹⁵ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NH₂, C(O)NHR¹⁶,C(O)N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHC(O)OR¹⁶, NR¹⁶C(O)OR¹⁶, OH, F,Cl, Br or I;

wherein each R¹⁶ is R¹⁷ or R^(17A);

R¹⁷ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R¹⁸, C(O)OH, NH₂,NHR¹⁸ or N(R¹⁸)₂, C(O)R^(is), C(O)NH₂, C(O)NHR¹⁸, C(O)N(R¹⁸)₂,NHC(O)R¹⁸, NR¹⁸C(O)R¹⁸, F, Cl, Br or I;

R^(17A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each R¹⁸ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

wherein each of the moieties represented by R¹², R¹³, R¹⁴, R^(17A), andR¹⁸ are independently unsubstituted or substituted with one or two orthree or four of independently selected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, OC(O)R¹⁹, OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹),NHC(O)R¹⁹, NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹, NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹,NR¹⁹C(O)OR¹⁹, NHC(O)NH₂, NHC(O)NHR¹⁹, NHC(O)N(R¹⁹)₂, NR¹⁹C(O)NHR¹⁹,NR¹⁹C(O)N(R¹⁹)₂, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹,C(O)NHSO₂R¹⁹, C(O)NR¹⁹SOR¹⁹, SO₂NH₂, SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR¹⁹, C(N)N(R¹⁹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³;

R²⁰ is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²¹ is heteroaryl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²² is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;each of which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R²³ is alkyl, alkenyl or alkynyl; each of which is unsubstituted orsubstituted with one or two of independently selected R²⁴, OR²⁴, SR²⁴,S(O)₂R²⁴, C(O)OH, NH₂, NHR²⁴N(R²⁴)₂, C(O)R²⁴, C(O)NH₂, C(O)NHR²⁴,C(O)N(R²⁴)₂, NHC(O)R²⁴, NR²⁴C(O)R²⁴, NHC(O)OR²⁴, NR¹⁴C(O)OR⁴,NHS(O)₂R²⁴, NR²⁴S(O)₂R²⁴, OH, F, Cl, Br or I;

wherein each R²⁴ is R^(24A) or R^(24B),

R^(24A) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl each of which is unfused or fusedwith benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkaneor heterocycloalkene;

R^(24B) is alkyl, alkenyl or alkynyl each of which is unsubstituted orsubstituted with one or two of independently selected R²⁵, OR²⁵, SR²⁵,S(O)₂R²⁵, C(O)OH, NH₂, NHR²⁵N(R²⁵)₂, C(O)R²⁵, C(O)NH₂, C(O)NHR²⁵,C(O)N(R²⁵)₂, NHC(O)R²⁵, NR²⁵C(O)R²⁵, NHC(O)OR²⁵, NR²⁵C(O)OR²⁵, OH, F,Cl, Br or I;

wherein each R²⁵ is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl; each of which is unsubstitutedor substituted with NH₂, NH(CH₃), N(CH₃)₂, OH or OCH₃;

wherein each of the moieties represented by R²⁰, R²¹, R²², and R^(24A)are independently unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶, alkenyl, alkynyl, phenyl, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I; and

R²⁶ is alkyl.

Embodiments of Formula I

Selected subclasses of compounds of interest that fall within the scopeof the compounds of formula I are shown in the various embodimentsdescribed below, wherein A¹, R¹, R^(A), R^(1A), R², R^(2A), A², R⁴, R⁵,R¹⁰, R^(10A), R^(10B), R^(10C), R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R^(17A), R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R^(24A), R^(24B), R²⁵ andR²⁶ can be as defined for the compounds of Formula I and as defined inthe various embodiments described throughout this specification.

Embodiments of A¹

In one embodiment of formula I, A¹ is R¹ or R², wherein R¹ is an unfusedcycloalkane and R² is an unfused heterocycloalkane, wherein A¹ isunsubstituted or is substituted with one or two OH, CN, C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl, cycloalkane, OR^(A) orNR^(A)R^(A); wherein R^(A) is H or alkyl. In another embodiment offormula I, A¹ is R¹ or R¹, wherein R¹ is cyclohexane and R² ispiperidinyl, wherein A¹ is unsubstituted or is substituted with one ortwo C_(L)-alkyl, C₂-alkyl or C₃-alkyl. In another embodiment of formulaI, A¹ is R¹ or R², wherein R¹ is unsubstituted cyclohexane and R² isunsubstituted piperidinyl. In another embodiment of formula I, A¹ is R¹,and R¹ is unsubstituted cyclohexane, as shown in formula (Ia):

Embodiments of A²

In one embodiment of formula I, A² is OR⁴, NHR⁴, N(R⁴)₂, SR⁴, S(O)R⁴,SO₂R⁴ or R⁵; wherein each R⁴ is C₁-alkyl, C₂-alkyl or C₃-alkyl; each ofwhich is substituted with R¹⁰ as described in Formula I; and R⁵ isC₁-alkyl, C₂-alkyl or C₃-alkyl wherein R⁵ is substituted as described informula I. In another embodiment of formula I, A² is R⁵, and R^(s) isC₁-alkyl, C₂-alkyl or C₃-alkyl wherein R⁵ is substituted as described informula I. In another embodiment of formula I, A² is R⁵, wherein R⁵ isC₁-alkyl, which is substituted with R¹⁰, and further unsubstituted orsubstituted with one or two or three of independently selected NHR¹⁰,N(R¹⁰)₂, SR¹⁰, S(O)R¹⁰, SO₂R¹⁰ or CF₃, wherein R¹⁰ is as described informula I. In another embodiment of formula I, A² is R⁵, wherein R⁵ isC₁-alkyl, substituted with R¹⁰ as described in Formula I and furtherunsubstituted as shown in formula (Ib):

In another embodiment of formula I, A² is R⁵, wherein R⁵ is C₂-alkyl,substituted with R¹⁰ as described in Formula I and further unsubstitutedas shown in formulas (Ic) and (Id):

In another embodiment of formula I, A² is R⁵, wherein R⁵ is C₃-alkyl,substituted with R¹⁰ as described in Formula I and furtherunsubstituted. In another embodiment of formula I, A² is R⁵, wherein R⁵is C₁-alkyl or C₂-alkyl; each of which are substituted with R¹⁰ asdescribed in Formula I and further substituted with CF₃.Embodiments of R¹⁰

In one embodiment of formula I, R¹⁰ is R^(10A), R^(10B) or R^(10C),wherein R^(10A) is phenyl which is unfused or fused withheterocycloalkane, which is fused heterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused, wherein R¹⁰ isoptionally substituted as described in Formula I. In another embodimentof formula I, R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) isphenyl which is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br,wherein R¹¹ is as described in Formula I. In another embodiment offormula I, R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) is phenylwhich is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; wherein R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused; R¹⁴ iscycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which isunfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene; each of which is unfused or fused with benzene; andR¹⁵ is alkyl which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I, wherein R¹⁶ is as described in Formula I. In another embodiment offormula I, R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) is phenylwhich is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; wherein R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused; R¹⁴ iscycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which isunfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene; each of which is unfused or fused with benzene; andR¹⁵ is alkyl which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl which isunsubstituted or substituted with R¹⁸; R^(17A) is phenyl, heteroaryl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which isunfused or fused with benzene or heterocycloalkane; and R¹⁸ is phenyl orheterocycloalkyl, which is unfused; wherein the moieties represented byR¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independently unsubstituted orsubstituted with one or two of independently selected R¹⁹, OR¹⁹, SR¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI, wherein R¹⁹ is as described in Formula I. In another embodiment offormula I, R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) is phenylwhich is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein each R¹¹ is R¹¹, R¹³, R¹⁴ or R¹⁵; wherein R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused;R¹⁴ is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of whichis unfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene; each of which is unfused or fused with benzene; andR¹⁵ is alkyl which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl which isunsubstituted or substituted with R¹⁸; R^(17A) is phenyl, heteroaryl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which isunfused or fused with benzene or heterocycloalkane: R¹⁸ is phenyl orheterocycloalkyl, which is unfused; wherein the moieties represented byR¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independently unsubstituted orsubstituted with one or two of independently selected R¹⁹, OR¹⁹, SR¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl, which isunfused; R²² is heteroaryl, which is unfused; R²³ is cycloalkyl orheterocycloalkyl; each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)R²⁴ or OH, wherein R²⁴ is as described in Formula I.In another embodiment of formula I, R¹⁰R^(10A), R^(10B) or R^(10C),wherein R^(10A) is phenyl which is unfused or fused withheterocycloalkane, which is fused heterocycloalkane, R^(10B) is

and R^(10B) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; wherein R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused;R¹⁴ is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of whichis unfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene: each of which is unfused or fused with benzene; andR¹⁵ is alkyl which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl which isunsubstituted or substituted with R¹⁸; R^(17A) is phenyl, heteroaryl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which isunfused or fused with benzene or heterocycloalkane; R¹⁸ is phenyl orheterocycloalkyl, which is unfused; wherein the moieties represented byR¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independently unsubstituted orsubstituted with one or two of independently selected R¹⁹, OR¹⁹, SR¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl, which isunfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkyl orheterocycloalkyl; each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶ (O), F, Cl, Br or I; and R²⁶ is alkyl. In another embodimentof formula I, R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) is

R^(10B) is

and R^(10C) is

wherein R¹⁰ is optionally substituted as described in Formula I. Inanother embodiment of formula I, R¹⁰ is R^(10A), wherein R^(10A) isphenyl which is unfused, wherein R¹⁰ is optionally substituted asdescribed in Formula I. In another embodiment of formula I, R¹⁰ isR^(10A), wherein R^(10A) is phenyl which is unfused, wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; wherein R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused;R¹⁴ is cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of whichis unfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene: each of which is unfused or fused with benzene; andR¹⁵ is alkyl which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl which isunsubstituted or substituted with R¹⁸; R^(17A) is phenyl, heteroaryl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which isunfused or fused with benzene or heterocycloalkane; R¹⁸ is phenyl orheterocycloalkyl, which is unfused; wherein the moieties represented byR¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independently unsubstituted orsubstituted with one or two of independently selected R¹⁹, OR¹⁹, SR¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl, which isunfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkyl orheterocycloalkyl: each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶(O), F, Cl, Br or I; and R²⁶ is alkyl. In another embodiment offormula I, R¹⁰ is R^(10A), wherein R^(10A) is phenyl which is unfused,wherein R¹⁰ is substituted with F and further substituted with NHC(O)R¹¹wherein R¹¹ is R¹⁵, wherein R¹⁶ is optionally substituted as describedin Formula I. In another embodiment of formula I, R¹⁰ is R^(10A),wherein R^(10A) is phenyl which is unfused, wherein R¹⁰ is substitutedwith F and further substituted with R¹¹, wherein R¹¹ is R¹² or R¹⁴,wherein R¹⁴ is heterocycloalkyl which is unsubstituted or substitutedwith one or two or three or four of independently selected R¹⁹, OR¹⁹,SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI, wherein R¹⁹ is as described in Formula I. In another embodiment offormula I, R¹⁰ is R^(10A), wherein R^(10A) is phenyl which is unfused,wherein R¹⁰ is substituted with F and further substituted with R¹¹,wherein R¹¹ is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl,hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl,imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl,tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which areindependently unsubstituted or substituted with one or two or three orfour of independently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹,CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹,C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is asdescribed in Formula I. In another embodiment of formula I, R¹⁰ isR^(10A), wherein R^(10A) is phenyl which is unfused, wherein R¹⁰ issubstituted with F and further substituted with R¹¹, wherein R¹¹ isphenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl,oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl,thiazinyl, azetidinyl, tetrahydropyrimidinyl, orazabicylo(2.2.1)hept-2-yl; each of which are independently substitutedwith one or two (O). In another embodiment of formula I, R¹⁰ is R^(10A),wherein R^(10A) is phenyl which is unfused, wherein R¹⁰ is substitutedwith F and further substituted with R¹¹, wherein R¹¹ is R¹⁴, wherein R¹⁴is heterocycloalkyl which is unsubstituted or substituted with one ortwo (O). In another embodiment of formula I, R¹⁰ is R^(10A), whereinR^(10A) is phenyl which is unfused, wherein R¹⁰ is substituted with Fand further substituted with R¹¹, wherein R¹¹ is R¹⁴, wherein R¹⁴ ispyrrolidinyl which is substituted with one or two or three or four ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹,NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂,C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is as described inFormula I and wherein R¹⁴ is substituted with at least one (O). Inanother embodiment of formula I, R¹⁰ is R^(10A), wherein R^(10A) isphenyl which is unfused, wherein R¹⁰ is substituted with F and furthersubstituted with R¹¹, wherein R¹¹ is R¹⁴, wherein R¹⁴ is pyrrolidinylwhich is substituted with one or two (O).Embodiments of Multiple Substituents

The following are additional embodiments of the compounds of Formula I.Unless otherwise specified, substituents are as described in Formula I.

In one embodiment of Formula I, R¹ is cycloalkane, which is unfused; R²is heterocycloalkane, which is unfused, and A¹ is R⁵.

Embodiments where A¹ is Cyclohexane, A² is R⁵

In one embodiment of Formula I, A¹ is R¹, wherein R¹ is unsubstitutedcyclohexane which is unfused, and A² is R⁵, which is as described inFormula I. In another embodiment of Formula I, A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ isC₁-alkyl, C₂-alkyl or C₃-alkyl wherein R⁵ is substituted as described inFormula I. In another embodiment of Formula I, A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ isC₁-alkyl, C₂-alkyl or C₃-alkyl wherein R¹⁰ is R^(10A), wherein isR^(10A) is phenyl which is unfused and substituted with F, and furthersubstituted with NHC(O)R¹¹, wherein R¹¹ is R¹⁵. In another embodiment ofFormula I, A¹ is R¹, wherein R¹ is unsubstituted cyclohexane which isunfused, and A² is R⁵, R⁵ is C₁-alkyl, C₂-alkyl or C₃-alkyl wherein R¹⁰is R^(10A), wherein is R^(10A) is phenyl which is unfused andsubstituted with F, and further substituted with NHC(O)R¹¹, wherein R¹¹is R¹⁵ wherein R¹⁵ is alkyl, which is unsubstituted or substituted withone or two of independently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH,NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl,Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl, which isunsubstituted or substituted with one or two of independently selectedR¹⁸; R^(17A) is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene orheterocycloalkane; wherein each R¹⁸ is phenyl or heterocycloalkyl;wherein each of the moieties represented by R^(17A) and R¹⁸ areindependently unsubstituted or substituted with one or two or three orfour of independently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹,CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹,C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I; wherein each R¹⁹is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl which is unfused; R²¹ isheteroaryl which is unfused; R²² is cycloalkyl or heterocycloalkyl; eachof which are unfused or fused with benzene; R²³ is alkyl, which isunsubstituted or substituted with one or two of independently selectedR²⁴, OR²⁴, NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A)or R²⁴; R^(24A) is unsubstituted phenyl, cycloalkyl, heterocycloalkyl orheterocycloalkenyl each of which is unfused or fused withheterocycloalkane; R^(24B) is alkyl, which is unsubstituted orsubstituted with one or two of independently selected OR²⁵ or OH;wherein each R²⁵ is alkyl unsubstituted or substituted with NH₂; whereineach R²⁰ is unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶, (O), F, Cl, Br or I; and R²⁶ is alkyl.In another embodiment of Formula I, A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ isC₁-alkyl, C₂-alkyl or C₃-alkyl wherein R¹⁰ is substituted with F, andfurther substituted with R¹⁴ wherein each R¹⁰ is independentlyunsubstituted or substituted with one or two or three of independentlyselected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, NHR¹¹, N(R¹¹)₂, C(O)R¹¹,C(O)OR¹¹, C(O)NH₂, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NR¹¹C(O)R¹¹,NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NR¹¹C(O)OR¹¹, NHSO₂NH₂, NHSO₂NHR¹¹,NHSO₂N(R¹¹)₂, SO₂NH₂, SO₂NHR¹¹, SO₂N(R¹¹)₂, NHC(O)NH₂, NHC(O)NHR¹¹,NHC(O)N(R¹¹)₂, NR¹¹C(O)N(R¹¹)₂, NO₂, OH, (O), C(O)H, C(O)OH, CN, CF₃,OCF₃, CF₂CF₃, F, Cl, Br or I; wherein R¹⁴ is pyrrolidinyl, azetidinyl,pyrrolyl, 1,3-oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl,tetrahydropyrimidin(2H)-yl, azabicyclo(2.2.1)heptyl or1,6-dihydropyridazyl; each of which unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; and wherein the moiety represented by R¹⁴ issubstituted with one or two (O) substituents. In another embodiment ofFormula I, A¹ is R¹, wherein R¹ is unsubstituted cyclohexane which isunfused, and A² is R⁵, R⁵ is C₁-alkyl, C₂-alkyl or C₃-alkyl wherein R⁵is substituted with R¹⁰, and further unsubstituted or substituted withone or two or three of independently selected NHR¹⁰, N(R¹⁰)₂, SR¹⁰,S(O)R¹⁰, SO₂R¹⁰ or CF₃, wherein R¹⁰ is as described in formula I. Inanother embodiment of Formula I, A¹ is R¹, wherein R¹ is unsubstitutedcyclohexane which is unfused, and A² is R⁵, R⁵ is C₁-alkyl, C₂-alkyl orC₃-alkyl wherein R⁵ is substituted with R¹⁰, and further unsubstitutedor substituted with one CF₃, wherein R¹⁰ is as described in formula I.In another embodiment of Formula I, A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵ selected fromthe following Formulas (Ie), (If), (Ig), (Ih), (Ii) or (Ij):

In one embodiment of Formula (Ii), R¹⁰ is R^(10A), R^(10B) or R^(10C);each of which must be attached at a carbon atom; R^(10A) is phenyl whichis unfused or fused with heterocycloalkane, which is fused withheterocycloalkane; R^(10B) is

R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with C(O)R¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂ or NHC(O)R¹¹, and isfurther unsubstituted or substituted with one or two or three ofindependently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂,C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl, Br orI; wherein each R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; R¹² is phenyl which isunfused or fused with benzene, heteroarene, heterocycloalkane orheterocycloalkene; R¹³ is heteroaryl, which is unfused; R¹⁴ iscycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which isunfused or fused with benzene, cycloalkane, heterocycloalkane orheterocycloalkene; each of which is unfused or fused with benzene; R¹⁵is alkyl, which is unsubstituted or substituted with one or two ofindependently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Bror I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl, which isunsubstituted or substituted with R¹⁵; R^(17A) is phenyl, heteroaryl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of which isunfused or fused with benzene or heterocycloalkane; R¹⁸ is phenyl orheterocycloalkyl, which is unfused; wherein the moieties represented byR¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independently unsubstituted orsubstituted with one or two independently selected R¹⁹, OR¹⁹, SR¹⁹,SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹), NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl, which isunfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkyl, orheterocycloalkyl each of which is unfused or fused with benzene; R²³ isalkyl which is unsubstituted or substituted with one or two ofindependently selected R²⁴, OR²⁴, NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴, OH, F, Cl,Br or I; wherein each R²⁴ is R^(24A) or R^(24B); R^(24A) is phenyl,cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each of which isunfused or fused with heterocycloalkane; R^(24B) is alkyl which isunsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵ is alkyleach of which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶, (O), F, Cl, Br or I; and R¹⁶ is alkyl. In another embodimentof Formula I, A¹ is R¹, wherein R¹ is unsubstituted cyclohexane which isunfused, and A² is R⁵, R⁵ is C₁-alkyl wherein R⁵ is substituted withR¹⁰, wherein R¹⁰ is as described in formula I, as described in Formula(Ie)

In another embodiment of Formula I, A¹ is R¹, wherein R¹ isunsubstituted cyclohexane which is unfused, and A² is R⁵, R⁵ isunbranched C₂-alkyl wherein R⁵ is substituted with R¹⁰, wherein R¹⁰ isas described in formula I, as described in Formula (If)

Embodiments of Formula (Ie)

In one embodiment of Formula (Ie), R¹⁰ is R^(10A), R^(10B) or R^(10C),wherein R^(10A) is phenyl which is unfused or fused withheterocycloalkane, which is fused heterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted as described in formula I. In another embodiment of Formula(Ie), R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) is phenylwhich is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with one or two of independently selected R¹¹, OR¹¹, SR¹¹,S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂,NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹ is as described inFormula I. In another embodiment of Formula (Ie), R¹⁰ is R^(10A),R^(10B) or R^(10C), wherein R^(10A) is phenyl which is unfused or fusedwith heterocycloalkane, which is fused heterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein R¹¹ is as described in Formula I. In another embodiment ofFormula (Ie), R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) isphenyl which is unfused or fused with heterocycloalkane, which is fusedheterocycloalkane, R^(10B) is

and R^(10C) is heterocycloalkyl, which is unfused; wherein R¹⁰ issubstituted with F and further unsubstituted or substituted with one ortwo of independently selected R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;wherein R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; R¹² is phenyl which is unfused orfused with benzene, heteroarene, heterocycloalkane or heterocycloalkene;R¹³ is heteroaryl, which is unfused; R¹⁴ is cycloalkyl, heterocycloalkylor heterocycloalkenyl; each of which is unfused or fused with benzene,cycloalkane, heterocycloalkane or heterocycloalkene; each of which isunfused or fused with benzene; R¹⁵ is alkyl which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶,NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷is alkyl which is unsubstituted or substituted with R^(is); R^(17A) isphenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene or heterocycloalkane; R¹⁸is phenyl or heterocycloalkyl, which is unfused; wherein the moietiesrepresented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independentlyunsubstituted or substituted with one or two of independently selectedR¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl,which is unfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkylor heterocycloalkyl; each of which is unfused or fused with benzene; R²³is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶ (O), F, Cl, Br or T; and R²⁶ is alkyl. In another embodimentof Formula (Ie), R¹⁰ is R^(10A), R^(10B) or R^(10C), wherein R^(10A) isphenyl which is unfused.

R^(10B) is

and R^(10C) is

wherein R¹⁰ is optionally substituted as described in Formula I. Inanother embodiment of Formula (Ie), R¹⁰ is R^(10A) R^(10B) or R^(10C) asdescribed in Formulas (Ik), (Il), (Im), (In), (Io) or (Ip)

wherein R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, and R¹⁰⁵, are independently selectedfrom R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹,C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹,NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹ is asdescribed in Formula I.

In another embodiment of Formula (Ie), R¹⁰ is R^(10A) or R^(10B), asdescribed in Formulas (Ik), (Il), (Im), (In), (Io) or (Ip). In anotherembodiment of Formula (Ie), R¹⁰ is phenyl, as shown in Formula (Ik):

wherein R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, and R¹⁰⁵, are independently selectedfrom H, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹,C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹,NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹is as described in Formula I. In another embodiment of Formula (Ik), atleast one of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, and R¹⁰⁵ are F, and at least one isR¹¹, wherein R¹¹ is phenyl, pyrrolyl, azabicyclo(3.1.0)hexanyl,hexahydro-1H-isoindolyl, 1,3-oxazolidinyl, azepanyl, piperidinyl,imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl,1,6-dihydropyridazyl, tetrahydropyrimidin(2H)-yl orazabicylo(2.2.1)hept-2-yl; each of which are independently unsubstitutedor substituted with one or two or three of independently selected R¹⁹,OR¹⁹SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl,which is unfused; R²¹ is heteroaryl, which is unfused; R²² iscycloalkyl, or heterocycloalkyl each of which is unfused or fused withbenzene; R²³ is alkyl which is unsubstituted or substituted with one ortwo of independently selected R²⁴, OR²⁴, NHR²⁴N(R²⁴)₂, NHS(O)₂R¹⁹, OH,F, Cl, Br or I; wherein each R²⁴ is R^(24A) or R^(24B); R^(24A) isphenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl; each ofwhich is unfused or fused with heterocycloalkane; R^(24B) is alkyl whichis unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵ isalkyl each of which is unsubstituted or substituted with NH₂; whereinthe moieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶, (O), F, Cl, Br or I; and R²⁶ is alkyl. In another embodimentof Formula (Ik), R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H, and R¹⁰² is R¹¹, wherein R¹¹is selected from pyrrolidinyl, oxazolyl, imidazolidinyl,isothiazolidinyl, piperidinyl, and azepanyl, wherein R¹⁰² is substitutedwith one or two (O) substituents. In another embodiment of Formula (Ik),R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H, and R¹⁰² is R¹¹, wherein R¹¹ is pyrrolidinyl.Further Embodiments of Formula (Ik)

In one embodiment of Formula (Ik), R¹⁰² is NHC(O)R¹¹, as described inFormula (Iq):

wherein R¹⁰¹, R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are independently selected from H,R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹,C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹, SO₂R¹¹, NHC(O)OR¹¹,NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹ is asdescribed in Formula I. In one embodiment of Formula (Iq), R¹¹ is R¹⁵,wherein R¹⁶ is optionally substituted as described in Formula I andR¹⁰¹, R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are as described in Formula (Iq). In anotherembodiment of Formula (Iq), R¹⁰³ is F, and R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ areindependently selected from H, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂,N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹,NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br;and R¹¹ is R¹⁵, wherein R¹⁶ is optionally substituted as described inFormula I. In another embodiment of Formula (Iq), one of R¹⁰¹, R¹⁰³,R¹⁰⁴ and R¹⁰⁵ is F, R¹¹ is R¹⁵, wherein R¹⁶ is optionally substituted asdescribed in Formula I. In another embodiment of Formula (Iq), R¹⁰¹,R¹⁰⁴ and R¹⁰⁵ is F. In another embodiment of Formula (Iq), R¹⁰³ is F. Inanother embodiment of Formula (Iq), one of R¹⁰¹, R¹⁰³, R¹⁰⁴ and R¹⁰⁵ isF, R¹¹ is R¹⁵, wherein R¹⁶ is alkyl, which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶,NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷is alkyl, which is unsubstituted or substituted with one or two ofindependently selected R¹⁸: R^(17A) is phenyl, heteroaryl, cycloalkyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene or heterocycloalkane; wherein each R¹⁸ is phenyl orheterocycloalkyl; wherein each of the moieties represented by R^(17A)and R¹⁸ are independently unsubstituted or substituted with one or twoor three or four of independently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹,C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂,C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I; whereineach R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl which is unfused; R²¹ isheteroaryl which is unfused; R²² is cycloalkyl or heterocycloalkyl; eachof which are unfused or fused with benzene; R²³ is alkyl, which isunsubstituted or substituted with one or two of independently selectedR²⁴, OR²⁴, NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A)or R^(24BA); R^(24A) is unsubstituted phenyl, cycloalkyl,heterocycloalkyl or heterocycloalkenyl each of which is unfused or fusedwith heterocycloalkane; R^(24B) is alkyl, which is unsubstituted orsubstituted with one or two of independently selected OR²⁵ or OH;wherein each R²⁵ is alkyl unsubstituted or substituted with NH₂; whereineach R²⁰ is unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶, (O), F, Cl, Br or I; and R²⁶ is alkyl.In another embodiment of Formula (Iq), R¹⁰³ is F, and R¹⁰¹, R¹⁰⁴ andR¹⁰⁵ are each H, R¹¹ is R¹⁵, wherein R¹⁶ is optionally substituted asdescribed in Formula I. In another embodiment of Formula (Iq), R¹¹ isR¹² or R¹⁴, wherein R¹⁴ is heterocycloalkyl which is unsubstituted orsubstituted with one or two or three or four of independently selectedR¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein R¹⁹ is as described in Formula I. In anotherembodiment of Formula (Iq), R¹¹ is selected from phenyl, pyrrolidinyl,azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl,azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl,azetidinyl, tetrahydropyrimidinyl or azabicylo(2.2.1)hept-2-yl; each ofwhich are independently unsubstituted or substituted with one or two orthree or four of independently selected R¹⁹OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹,CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹,C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I; wherein R¹⁹ is asdescribed in Formula I.

In one embodiment of Formula (Ik), R¹⁰² is R¹¹, wherein R¹¹ ispyrrolidinyl as described in Formula (Ir):

wherein R¹⁰¹, R¹⁰³, R¹⁰⁴, and R¹⁰⁵, are independently selected from H,R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹,C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹,NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹ is asdescribed in Formula I, and R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are independentlyH, R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂,NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O),CN, CF₃, F, Cl, Br or I; wherein R¹⁹ is as described in Formula I. Inone embodiment of Formula (Ir), R¹⁰³ is F, and R¹⁰¹, R¹⁰⁴, and R¹⁰⁵ areH, wherein R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are independently H, R¹⁹, OR¹⁹,SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br orI; wherein R¹⁹ is as described in Formula I. In one embodiment ofFormula (Ir), one or two of R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ is (O). Inanother embodiment of Formula (Ir), two of R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴are (O). In another embodiment of Formula (Ir), R²⁰¹ and R²⁰⁴ are (O)and R²⁰² and R²⁰³ are H, as described in Formula (Ir₁):

In one embodiment of Formula (Ir₁), R¹⁰³ is F and R¹⁰¹, R¹⁰⁴, and R¹⁰⁵,are independently selected from H, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹,NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹,NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F,Cl or Br; wherein R¹¹ is as described in Formula I.

In one embodiment of Formula (Ik), R¹⁰³ is F, as described in Formula(Is):

wherein R¹⁰¹, R¹⁰², R¹⁰⁴, and R¹⁰⁵, are independently selected from H,R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹,C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹,NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein R¹¹ is asdescribed in Formula I. In another embodiment of Formula (Is), R¹⁰¹,R¹⁰², R¹⁰⁴, and R¹⁰⁵, are independently selected from H, R¹¹, OR¹¹,SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹, C(O)OR¹¹, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹, NHC(O)OR¹¹, NHSON(R¹¹)₂,NO₂, OH, (O), C(O)OH, F, Cl or Br; wherein each R¹¹ is R¹², R¹³, R¹⁴ orR¹⁵; wherein R¹² is phenyl which is unfused or fused with benzene,heteroarene, heterocycloalkane or heterocycloalkene; R¹³ heteroaryl,which is unfused; R¹⁴ is cycloalkyl, heterocycloalkyl orheterocycloalkenyl; each of which is unfused or fused with benzene,cycloalkane, heterocycloalkane or heterocycloalkene; each of which isunfused or fused with benzene; and R¹⁵ is alkyl which is unsubstitutedor substituted with one or two of independently selected R¹⁶, OR¹⁶,SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶,NHC(O)R¹⁶, NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ orR^(1A); R¹⁷ is alkyl which is unsubstituted or substituted with R's;R^(17A) is phenyl, heteroaryl, cycloalkyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene orheterocycloalkane: R¹⁸ is phenyl or heterocycloalkyl, which is unfused;wherein the moieties represented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ areindependently unsubstituted or substituted with one or two ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹,NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂,C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹,R²² or R²³; R²⁰ is phenyl, which is unfused; R²¹ is heteroaryl, which isunfused; R²² is cycloalkyl or heterocycloalkyl; each of which is unfusedor fused with benzene; and R²³ is alkyl which is unsubstituted orsubstituted with R²⁴, OR²⁴, NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein eachR²⁴ is R^(24A) or R²⁴; R^(24A) is phenyl, cycloalkyl, heterocycloalkylor heterocycloalkenyl, which is unfused or fused with heterocycloalkane;R^(24B) is alkyl, which is unsubstituted or substituted with OR²⁵, OH,F, Cl, Br or I; R²⁵ is alkyl, which is unsubstituted or substituted withNH₂; wherein the moieties represented by R²⁰, R²¹, R²², and R^(24A) areindependently unsubstituted or substituted with one or two ofindependently selected R²⁶, OR²⁶ (O), F, Cl, Br or I; and R²⁶ is alkyl.In another embodiment of Formula (Is), R¹¹ is selected from phenyl,pyrrolidinyl, azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl,oxazolidinyl, azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl,thiazinyl, azetidinyl, tetrahydropyrimidinyl orazabicylo(2.2.1)hept-2-yl; each of which are independently unsubstitutedor substituted with one or two or three or four of independentlyselected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂,NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O),CN, CF₃, F, Cl, Br or I; wherein R¹⁹ is as described in Formula I. Inanother embodiment of Formula (Is), R¹⁰² is R¹¹, wherein R¹¹ is selectedfrom pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl,piperidinyl, piperazinyl and azepanyl, wherein R¹⁰² is substituted withone or two (O) substituents. In another embodiment of Formula (Is), R¹⁰²is R¹¹, wherein R¹¹ is selected from pyrrolidinyl substituted with oneor two (O) substituents. In another embodiment of Formula (Is), R¹⁰¹,R¹⁰⁴ and R¹⁰⁵ are H, and R¹⁰² is selected from R¹¹, OR¹¹, NHC(O)R¹¹, orC(O)NHR¹¹; wherein R¹¹ is as described in Formula I. In anotherembodiment of Formula (Is), wherein R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H, and R¹⁰²is selected from R¹¹, OR¹¹, NHC(O)R¹¹, or C(O)NHR¹¹;

wherein R¹¹ is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl,hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl,imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl,tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which areindependently unsubstituted or substituted with one or two or three orfour of independently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹,CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹,C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is asdescribed in Formula I. In another embodiment of Formula (Is), whereinR¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H, and R¹⁰² is selected from R¹¹, OR¹¹,NHC(O)R¹¹, or C(O)NHR¹¹; wherein R¹¹ is phenyl, pyrrolidinyl,azabicyclo(3.1.0)hexanyl, hexahydro-1H-isoindolyl, oxazolidinyl,azepanyl, piperidinyl, imidazolidinyl, thiazolidinyl, thiazinyl,azetidinyl, tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each ofwhich are independently unsubstituted or substituted with one or two ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹,NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂,C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is as described inFormula I. In another embodiment of Formula (Is), wherein R¹⁰¹, R¹⁰⁴ andR¹⁰⁵ are H, and R¹⁰² is selected from R¹¹, OR¹¹, NHC(O)R¹¹, orC(O)NHR¹¹; wherein R¹¹ is R¹⁵ and R¹⁵ is alkyl which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶,NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷is alkyl which is unsubstituted or substituted with R¹⁸; R^(17A) isphenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene or heterocycloalkane; R¹⁸is phenyl or heterocycloalkyl, which is unfused; wherein the moietiesrepresented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independentlyunsubstituted or substituted with one or two of independently selectedR¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²¹; R²⁰ is phenyl,which is unfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkylor heterocycloalkyl; each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶(O), F, Cl, Br or I; and R²⁶ is alkyl.

In one embodiment, the compound of Formula (Is) is selected from:

-   2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoic    acid;-   4-(3-amino-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)amino)-4-oxobutanoic    acid;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   4-(3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(aminomethyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((dimethylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-((cyclohexylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-(2H)-one;-   4-(4-fluoro-3-((tetrahydro-2H-pyran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((methyl((1-methylpyrrolidin-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((methyl(((2R)-1-methylpyrrolidin-2-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-pyrimidin-2-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-(2H)-one;-   4-(4-fluoro-3-pyridin-3-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-pyridin-4-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N,N-diethyl-2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-2-carboxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-piperidin-1-ylpropanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide;-   2-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide;-   3-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-3-carboxamide;-   4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-3-carboxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-morpholin-4-ylacetamide;-   N-(2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-3-yl)acetamide;-   4-((6-fluoro-3′-(methylsulfonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-((6-fluoro-4′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N,N-diethyl-2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-3-carboxamide;-   2′-fluoro-N,N-dimethyl-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-4-carboxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione;-   3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;-   2-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione;-   4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazepan-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-2,6-dione;-   4-(4-fluoro-3-(2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(1,1-dioxidoisothiazolidin-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-(3-tert-butyl-2-oxoimidazolidin-1-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N-methylmethanesulfonamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-hydroxy-2-methylpropanamide;-   (3aS,4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-dimethyltetrahydro-4,7-methano(1,3)dioxolo(4,5-c)pyridin-6(3aH)-one;-   4-(3-(1,1-dioxido-1,2-thiazinan-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(2-oxopyrrolidin-1-yl)acetamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carb    oxamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-oxohexanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-methoxypropanamide;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N′-phenylpentanediamide;-   4-(4-fluoro-3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-N-dimethylpiperazine-11-carboxamide;-   4-(4-fluoro-3-{[4-(piperazin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-4-carboxamide;-   4-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide;-   4-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N,N-diethyl-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide;-   4-(3-{[4-(3-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4({[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(2-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N,N-diethyl-4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxamide;-   4-{4-fluoro-3-[(4-isopropylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-isopropylurea;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-propylurea;-   N-cyclopentyl-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   N-(2,4-difluorophenyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   N-(tert-butyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea;-   benzyl    4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxylate;-   benzyl    4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate;-   4-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl)}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   4-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-ethylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   benzyl    (3S)-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-2,5-dioxopyrrolidin-3-ylcarbamate;-   (3S)-3-amino-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}pyrrolidine-2,5-dione;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-4-methylpiperazine-1-carboxamide;-   4-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl})—N-methyl-N-phenylurea;-   N-ethyl-N-(1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}pyrrolidin-3-yl)acetamide;-   4-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]glycine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]leucine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]alanine;-   N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]phenylalanine;-   3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;-   4(3-{[4-(cyclopropylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methylcyclopropyl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-4-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   5-benzyl-3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;-   4-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(5-oxopyrrolidin-2-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{3-[(4-{[(4R)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl}piperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(3-{[4(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-(methylamino)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   tert-butyl 2-(ethyl    {2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethylcarbamate;-   2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide;-   N-(2-aminoethyl)-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   4-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide;-   4-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[3-({4-[(5-chloro-6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-([1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl)piperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-[2-(benzoylamino)ethyl]-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N-[2-(ethyl    {2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethyl]pyrrolidine-1-carboxamide;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methylcyclobutanecarboxamide;-   4-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;-   N-{2-[(2,6-difluorobenzoyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide;    or-   N-[2-(ethyl{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethyl]nicotinamide.

In another embodiment, the compound of Formula (Is) is selected from

-   4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)amino)-4-oxobutanoic    acid;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide;-   3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione;-   4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxoazepan-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-2,6-dione;-   4-(3-(1,1-dioxidoisothiazolidin-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   4-(4-fluoro-3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one;-   benzyl    (3S)-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-2,5-dioxopyrrolidin-3-ylcarbamate;-   (3S)-3-amino-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}pyrrolidine-2,5-dione;-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-4-methylpiperazine-1-carboxamide;-   3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;-   5-benzyl-3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione;    or-   N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methylcyclobutanecarboxamide.

In one embodiment of Formula (Ik), R¹⁰² is C(O)R¹¹, as described inFormula (It):

wherein R¹¹ is as described in Formula I. In one embodiment of Formula(It), R¹⁰¹, R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are H. In another embodiment of Formula(It), R¹⁰³ is F and R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H. In another embodiment ofFormula (It), R¹¹ is R¹⁵ and R¹⁵ is alkyl which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶,NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷is alkyl which is unsubstituted or substituted with R¹⁸; R^(17A) isphenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene or heterocycloalkane; R¹⁸is phenyl or heterocycloalkyl, which is unfused; wherein the moietiesrepresented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independentlyunsubstituted or substituted with one or two of independently selectedR¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl,which is unfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkylor heterocycloalkyl; each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R¹⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶ (O), F, Cl, Br or I; and R²⁶ is alkyl. In another embodimentof Formula (It), R¹¹ is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl,hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl,imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl,tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which areindependently unsubstituted or substituted with one or two ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹,NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂,C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is as described inFormula I.

In one embodiment of Formula (Ik), R¹⁰² is C(O)NHR¹¹, as described inFormula (Iu):

wherein R¹¹ is as described in Formula I. In one embodiment of Formula(Iu), R¹⁰¹, R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are H. In another embodiment of Formula(Iu), R¹⁰³ is F and R¹⁰¹, R¹⁰⁴ and R¹⁰⁵ are H. In another embodiment ofFormula (Iu), R¹¹ is R¹⁵ and R¹⁵ is alkyl which is unsubstituted orsubstituted with one or two of independently selected R¹⁶, OR¹⁶, SR¹⁶,S(O)₂R¹⁶, C(O)OH, NH₂, NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NHR¹⁶, NHC(O)R¹⁶,NHC(O)OR¹⁶, OH, F, Cl, Br or I; wherein each R¹⁶ is R¹⁷ or R^(17A); R¹⁷is alkyl which is unsubstituted or substituted with R¹⁸; R^(17A) isphenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene or heterocycloalkane; R¹⁸is phenyl or heterocycloalkyl, which is unfused; wherein the moietiesrepresented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ are independentlyunsubstituted or substituted with one or two of independently selectedR¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)H, OH, (O), CN, CF₃, F,Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³; R²⁰ is phenyl,which is unfused; R²¹ is heteroaryl, which is unfused; R²² is cycloalkylor heterocycloalkyl; each of which is unfused or fused with benzene; andR²³ is alkyl which is unsubstituted or substituted with R²⁴, OR²⁴,NHR²⁴N(R²⁴)₂, NHS(O)₂R²⁴ or OH; wherein each R²⁴ is R^(24A) or R^(24B);R^(24A) is phenyl, cycloalkyl, heterocycloalkyl or heterocycloalkenyl,which is unfused or fused with heterocycloalkane; R^(24B) is alkyl,which is unsubstituted or substituted with OR²⁵, OH, F, Cl, Br or I; R²⁵is alkyl, which is unsubstituted or substituted with NH₂; wherein themoieties represented by R²⁰, R²¹, R²², and R^(24A) are independentlyunsubstituted or substituted with one or two of independently selectedR²⁶, OR²⁶ (O), F, Cl, Br or I; and R²⁶ is alkyl. In another embodimentof Formula (Iu), R¹¹ is phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanyl,hexahydro-1H-isoindolyl, oxazolidinyl, azepanyl, piperidinyl,imidazolidinyl, thiazolidinyl, thiazinyl, azetidinyl,tetrahydropyrimidinyl, or azabicylo(2.2.1)hept-2-yl; each of which areindependently unsubstituted or substituted with one or two ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹,NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NHS(O)₂R¹⁹, C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂,C(O)H, OH, (O), CN, CF₃, F, Cl, Br or I wherein R¹⁹ is as described inFormula I.

In one embodiment of Formula (Ik), R¹⁰² is phenyl which is unsubstitutedor substituted with one or two or three or four of independentlyselected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹, SO₂R¹⁹, C(O)R¹⁹, CO(O)R¹⁹, OC(O)R¹⁹,OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹, NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹,NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹, NR¹⁹C(O)OR¹⁹, NHC(O)NH₂, NHC(O)NHR¹⁹,NHC(O)N(R¹⁹)₂, NR¹⁹C(O)NHR¹⁹, NR¹⁹C(O)N(R¹⁹)₂, C(O)NH₂, C(O)NHR¹⁹,C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹, C(O)NHSO₂R¹⁹, C(O)NR¹⁹SO₂R¹⁹, SO₂NH₂,SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹⁹, C(N)N(R¹⁹)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I; wherein R¹⁹ is as described in Formula I.

In one embodiment of Formula (Ik), R¹⁰² is heterocycloalkyl which isunsubstituted or substituted with one or two or three or four ofindependently selected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹, SO₂R¹⁹, C(O)R¹⁹,CO(O)R¹⁹, OC(O)R¹⁹, OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹, NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹, NR¹⁹C(O)OR¹⁹,NHC(O)NH₂, NHC(O)NHR¹⁹, NHC(O)N(R¹⁹)₂, NR¹⁹C(O)NHR¹⁹, NR¹⁹C(O)N(R¹⁹)₂,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹, C(O)NHSO₂R¹⁹,C(O)NR¹⁹SOR¹⁹, SO₂NH₂, SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR¹⁹, C(N)N(R¹⁹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I; wherein R¹⁹ is as described in Formula I.

Embodiments where A¹⁰² is Piperidine, A² is R⁵

In one embodiment of Formula (I) A¹ is R², wherein R² is unsubstitutedpiperidine which is unfused, and A² is R⁵, which is as described inFormula I. In another embodiment of Formula I, A¹ is R², wherein R² isunsubstituted piperidine which is unfused, and A² is R⁵, R⁵ is C₁-alkyl,C₂-alkyl or C₃-alkyl wherein R⁵ is substituted with R¹⁰, and furtherunsubstituted or substituted with one or two or three of independentlyselected NHR¹⁰, N(R¹⁰)₂, SR¹⁰, S(O)R¹⁰, SO₂R¹⁰ or CF₃, wherein R¹⁰ is asdescribed in formula I. In another embodiment of Formula I, A¹ is R²,wherein R¹ is unsubstituted piperidine which is unfused, and A² is R⁵,R⁵ is C₁-alkyl, C₂-alkyl or C₃-alkyl wherein R⁵ is substituted with R¹⁰,and further unsubstituted or substituted with one CF₃, wherein R¹⁰ is asdescribed in formula I. In another embodiment of Formula I, A¹ is R²,wherein R² is unsubstituted piperidine which is unfused, A² is C₁-alkyl,and R¹⁰ is phenyl, as shown in Formula (Iv):

wherein R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, and R¹⁰⁵, are independently selectedfrom H, R¹¹, OR¹¹, SR¹¹, S(O)R¹¹, SO₂R¹¹, NH₂, N(R¹¹)₂, C(O)R¹¹,C(O)OR¹¹, C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHSO₂R¹¹, NR¹¹SO₂R¹¹,NHC(O)OR¹¹, NHSO₂N(R¹¹)₂, NO₂, OH, (O), C(O)OH, F, Cl or Br; whereineach R¹¹ is R¹², R¹³, R¹⁴ or R¹⁵; R¹² is phenyl which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹³ is heteroaryl which isunfused or fused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁴ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁵ is alkyl, alkenyl oralkynyl; each of which is unsubstituted or substituted with one or twoof independently selected R¹⁶, OR¹⁶, SR¹⁶, S(O)₂R¹⁶, C(O)OH, NH₂,NHR¹⁶N(R¹⁶)₂, C(O)R¹⁶, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, NHC(O)R¹⁶,NR¹⁶C(O)R¹⁶, NHC(O)OR¹⁶, NR¹⁶C(O)OR¹⁶, OH, F, Cl, Br or I; wherein eachR¹⁶ is R¹⁷ or R^(17A); R¹⁷ is alkyl, alkenyl or alkynyl: each of whichis unsubstituted or substituted with one or two of independentlyselected R¹⁸, C(O)OH, NH₂, NHR¹⁸ or N(R¹⁸)₂, C(O)R¹⁸, C(O)NH₂,C(O)NHR¹⁸, C(O)N(R¹⁸)₂, NHC(O)R¹⁸, NR¹⁸C(O)R¹⁸, F, Cl, Br or I; R^(17A)is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; wherein each R¹⁸ is phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; wherein each ofthe moieties represented by R¹², R¹³, R¹⁴, R^(17A), and R¹⁸ areindependently unsubstituted or substituted with one or two or three orfour of independently selected R¹⁹, OR¹⁹, SR¹⁹, S(O)R¹⁹, SO₂R¹⁹,C(O)R¹⁹, CO(O)R¹⁹, OC(O)R¹⁹, OC(O)OR¹⁹, NH₂, NHR¹⁹, N(R¹⁹)₂, NHC(O)R¹⁹,NR¹⁹C(O)R¹⁹, NHS(O)₂R¹⁹, NR¹⁹S(O)₂R¹⁹, NHC(O)OR¹⁹, NR¹⁹C(O)OR¹⁹,NHC(O)NH₂, NHC(O)NHR¹⁹, NHC(O)N(R¹⁹)₂, NR¹⁹C(O)NHR¹⁹, NR¹⁹C(O)N(R¹⁹)₂,C(O)NH₂, C(O)NHR¹⁹, C(O)N(R¹⁹)₂, C(O)NHOH, C(O)NHOR¹⁹, C(O)NHSO₂R¹⁹,C(O)NR¹⁹SO₂R¹⁹, SO₂NH₂, SO₂NHR¹⁹, SO₂N(R¹⁹)₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR¹⁹, C(N)N(R¹⁹)₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃,OCF₃, OCF₂CF₃, F, Cl, Br or I; wherein each R¹⁹ is R²⁰, R²¹, R²² or R²³;R²⁰ is phenyl which is unfused or fused with benzene, heteroarene,cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; eachof which is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R²¹ is heteroarylwhich is unfused or fused with benzene, heteroarene, cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; each of which isunfused or fused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²² is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is unfused orfused with benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²³ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoof independently selected R²⁴, OR²⁴, SR²⁴, S(O)₂R²⁴, C(O)OH, NH₂,NHR²⁴N(R²⁴)₂, C(O)R²⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R¹⁴)₂, NHC(O)R¹⁴,NR²C(O)R²⁴, NHC(O)OR⁴, NR¹⁴C(O)OR¹⁴, NHS(O)₂R²⁴, NR⁴S(O)₂R²⁴, OH, F, Cl,Br or I; wherein each R²⁴ is R^(24A) or R^(24B); R^(24A) is phenyl,heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl each of which is unfused or fused with benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R^(24B) is alkyl, alkenyl or alkynyl each of which isunsubstituted or substituted with one or two of independently selectedR²⁵, OR²⁵, SR²⁵, S(O)₂R²⁵, C(O)OH, NH₂, NHR²⁵N(R²⁵)₂, C(O)R²⁵, C(O)NH₂,C(O)NHR²⁵, C(O)N(R²⁵)₂, NHC(O)R²⁵, NR²⁵C(O)R⁵, NHC(O)OR²⁵, NR²⁵C(O)OR²,OH, F, Cl, Br or I; wherein each R²⁵ is alkyl, phenyl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; eachof which is unsubstituted or substituted with NH₂, NH(CH₃), N(CH₃)₂, OHor OCH₃; wherein each of the moieties represented by R²⁰, R²¹, R²², andR^(24A) are independently unsubstituted or substituted with one or twoof independently selected R²⁶, OR²⁶, alkenyl, alkynyl, phenyl, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I; and R²⁶ is alkyl. Inanother embodiment, the compound of Formula (Iv) is selected from

-   8-(4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   8-(3-chloro-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one-   8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   methyl    2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoate;-   8-(3-amino-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoic    acid;-   N-ethyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   N-cyclobutyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide;-   8-(4-fluoro-3-((4-(morpholin-4-ylcarbonyl)piperazin-1-yl)carbonyl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-N′-phenylpentanediamide;-   1-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidine-2,5-dione;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methy)phenyl)-3-methoxypropanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-5-oxohexanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-phenoxypropanamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methy)phenyl)-4-oxo-4-phenylbutanamide;-   2-(4-(benzyloxy)phenoxy)-N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)acetamide;-   N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-2-(4-methoxyphenoxy)acetamide;-   N-cyclopropyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;-   8-(3-((4-(2-ethoxyethyl)piperazin-1-yl)carbonyl)-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one;-   2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-piperidin-1-ylethyl)benzamide;-   8-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}piperidine-2,6-dione;-   8-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-N,N-dimethylpiperazine-1-carboxamide;-   N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   8-{4-fluoro-3-[(4-methylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-3-carboxamide;-   8-(4-fluoro-3-{[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-4    carboxamide;-   8-(4-fluoro-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-2-morpholin-4-ylpiperazine-1-carbaldehyde;-   8-(4-fluoro-3-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   N,N-diethyl-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxamide;-   8-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-(4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazin-1-yl)-N,N-dimethylacetamide;-   8-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   8-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-piperidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-isopropylimidazolidine-2,4-dione;-   8-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[44(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidin-3-yl)-N-methylacetamide;-   N-ethyl-N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidin-3-yl)acetamide;-   8-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-methylimidazolidine-2,4-dione;-   8-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-(4-[3-(trifluoromethyl)phenyl]piperazin-1-yl)    carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   tert-butyl    3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}tetrahydropyrimidine-1(2H)-carboxylate;-   8-{4-([3-[3-(dimethylamino)propyl]tetrahydropyrimidin-1(2H)-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   5-benzyl-3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}imidazolidine-2,4-dione;-   3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione;-   8-{4-fluoro-3-[(3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{3-[(4-benzoylpiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(3-chlorobenzoyl)piperidin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   benzyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate;-   tert-butyl    (3R)-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-3-phenylpiperazine-1-carboxylate;-   8-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[(2R)-2-phenylpiperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(cyclopentylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(5-chloropyridin-2-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-{[1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(6-chloro-5-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-6-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   benzyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate;-   8-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   ethyl    4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate;-   8-{3-[(2,2-dimethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-isonicotinoyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-isonicotinoyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(3-{[4-(1H-benzimidazol-6-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(4-fluorobenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-[3-({4-[(5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]piperazin-1-yl}carbonyl-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(2-furoyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   tert-butyl    4-[{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}(methyl)amino]piperidine-1-carboxylate;-   tert-butyl    4-({2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}amino)piperidine-1-carboxylate;-   tert-butyl    1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-ylcarbamate;-   8-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   8-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide;-   8-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one;-   2-fluoro-N-(4-hydroxycyclohexyl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide,-   N-[1-(1H-benzimidazol-5-ylcarbonyl)piperidin-4-yl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide;-   2-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   N-[(1S,2S)-2-aminocyclohexyl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide;-   2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-(1-pyridin-2-ylpiperidin-4-yl)benzamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)pyridine-2-carboxamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)nicotinamide,-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)isonicotinamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-indazole-6-carboxamide;-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-2-furamide;-   N-(1-({2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1,3-thiazole-4-carboxamide;    or-   N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-pyrazole-4-carboxamide.

SCHEMES

The starting materials used herein are commercially available or may beprepared by routine methods well known to those of ordinary skill in theart. The compounds of the present invention may be prepared using themethods illustrated in the general synthetic schemes and experimentalprocedures detailed below. The general synthetic schemes are presentedfor purposes of illustration and are not intended to be limiting.

As shown in Scheme 1, the bicyclic anhydride (1) can be reduced to thealcohol (2) using a reducing agent such as but not limited to sodiumborohydride. The reaction is typically conducted in a solvent such asbut not limited to tetrahydrofuran at below room temperature to reflux.Conversion of (2) to the phosphonium salt (3) may be carried out byreacting the former with a trialkyl phosphine such as but not limited totri-n-butyl phosphine in the presence of hydrobromic acid. The reactionis typically conducted in a solvent such as but not limited to aceticacid at reflux. Reaction of (3) with a nitrobenzaldehyde of Formula (4),wherein R^(11A) is a substituent on R¹⁰ as described herein, in thepresence of a base such as but not limited to triethylamine will providea lactone of Formula (5). The reaction is typically conducted in asolvent such as but not limited to dichloromethane at room temperature.Reduction of the nitro group of a compound of Formula (5) with areducing agent such as but not limited to iron powder and NH₄Cl willprovide the corresponding aniline of Formula (6). The reaction istypically conducted in a solvent such as but not limited to ethanol atreflux. Reaction of the aniline of Formula (6) with hydrazine willprovide a tetrahydrophthalazinone of Formula (7). The reaction istypically conducted in a solvent such as but not limited to ethanol atan elevated temperature. Reaction of a compound of Formula (7) witheither an anhydride of Formula (8) or with an acid of Formula (11) understandard peptide coupling conditions known to those skilled in the artand widely available in the literature will provide compounds of Formula(9) and (12), respectively. An acid of Formula (9) may be furthermodified to an imide of Formula (10) using standard peptide couplingconditions including the use of 1,1′-carbonyldiimidazole (CDI) as thecoupling agent.

Alternatively, as shown in Scheme 2, the phosphonium salt (3) can bereacted with a cyanobenzaldehyde of Formula (13) to provide a lactone ofFormula (14). The reaction is typically conducted under basic conditionsin a solvent such as but not limited to dichloromethane at roomtemperature. Hydrolysis of the nitrile of Formula (14) to thecorresponding acid, followed by addition of hydrazine will provide thetetrahydrophthalazinone of Formula (15). The hydrolysis step istypically conducted with an aqueous base such as but not limited tosodium hydroxide at elevated temperatures. The second step is alsoconducted under aqueous conditions at elevated temperatures. Couplingthe acid of Formula (15) with an amine of Formula (16), wherein each R¹¹is as described in Formula I herein or is H or is a heterocyclic amineR¹⁴, under standard peptide coupling conditions known to those skilledin the art and widely available in the literature, will provide an amideof Formula (17). Alternatively, a compound of Formula (14) can beconverted to a tetrahydrophthalazinone using hydrazine as previouslydescribed, followed by reduction to the primary amine of Formula (18)under standard Raney-nickel reduction conditions. Treatment of compoundsof Formula (18) under standard reductive amination conditions with analdehyde R¹⁶CHO or ketone R¹⁶C(O)R¹⁶ and then optionally with a secondaldehyde R¹⁶CHO or ketone R¹⁶C(O)R¹⁶, will provide secondary or tertiaryamines of Formula (19) (wherein each R¹⁶ can be H or as defined inFormula (I)).

In a manner similar to the procedure described in Scheme I, thephosphonium salt (3) can be reacted with a benzaldehyde of Formula (20),wherein R^(11B) is alkyl such as but not limited to ethyl and R^(11A) isas previously defined in Scheme 1. Reaction of a compound of Formula(21) with hydrazine as described in Scheme 1, followed by hydrolysisusing an aqueous acid such as but not limited to sulfuric acid willprovide a compound of Formula (22). The reaction is typically performedat elevated temperatures in a solvent such as but not limited totethanol. Reaction of a compound of Formula (22) with an amine of Formula(23) under reductive amination conditions known to those skilled in theart and widely available in the literature will provide atetrahydrophthalazinone of Formula (19).

As shown in Scheme 4, the phosphonium salt (3) can be reacted with abromobenzaldehyde of Formula (24) to provide a compound of Formula (25)using the conditions described in Scheme 1. Reaction of a compound ofFormula (25) with hydrazine as described in Scheme 1 will provide atetrahydrophthalazinone of Formula (26), which can be coupled withstannane of Formula (27) or a borate of Formula (28) to provide acompound of Formula (29) wherein R¹¹ is a substituted or unsubstitutedphenyl or heteroaryl. Coupling conditions include those known by thoseskilled in the art and widely available in the literature for Suzuki andStille type couplings.

A benzylic bromide of Formula (30) wherein R¹¹ is as described herein,can be converted to a Grignard reagent and then added to a diester (31)to give a keto-ester of Formula (32) as shown in Scheme 5. The additionof the Grignard reagent is typically performed at cold temperatures,before warming up the reaction to room temperature. The reaction istypically performed in a solvent such as but not limited totetrahydrofuran, ether and the like, or mixtures thereof. The Grignardreagent may be purchased commercially or prepared from Mg using standardconditions available in the literature. The addition of hydrazine to acompound of Formula (32) under conditions described in Scheme I at roomtemperature will provide a phthalazinone of Formula (33). The bromidecan be converted to an ester of Formula (34) under palladium catalyzedcarboxylation conditions. The transformation typically requires the useof a palladium catalyst and a base, such as but not limited totriethylamine, in addition to carbon monoxide and methanol. Typicalpalladium catalysts include[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane and the like. The reaction is typically conducted atelevated temperatures and may require the use of a solvent such as butnot limited to N,N-dimethylformamide. The ester of Formula (34) can beconverted to a primary amide of Formula (35) using ammonia, followed bya Hoffman rearrangement with bromine and aqueous potassium hydroxide toprovide an aniline of Formula (36). The first step typically requires anelevated temperature, and the second step typically requires a decreasedtemperature for the additions, followed by heating. The pyridine ringcan be reduced under catalytic conditions, such as but not limited tothe use of hydrogen gas and platinum on carbon to provide a compound ofFormula (37). Amide formation using either an acid chloride of FormulaR¹¹C(O)Cl or an acid of Formula R¹¹C(O)OH under standard peptidecoupling conditions known to those skilled in the art and widelyavailable in the literature will provide compounds of Formula (38).Alternatively, an ester of Formula (34) can be reduced to a compound ofFormula (39) using the conditions described above, followed byhydrolysis to provide an acid of Formula (40). Typical hydrolysisconditions include but are not limited to using an aqueous base such aslithium hydroxide at elevated temperatures. Amide formation using aprimary or secondary amine of Formula NH₂R¹¹ or NH(R¹¹)₂ employingstandard peptide coupling conditions known to those skilled in the artand widely available in the literature, will provide an amide of Formula(41).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), except for Examples 160, 320 and487, which were named using ChemDraw) Ver. 9.0.5 (CambridgeSoft,Cambridge, Mass.). Intermediates were named using IUPAC standards.

Example 12-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoicacid Example 1A 3-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one

To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g) intetrahydrofuran (125 mL) at 0° C. was added sodium borohydride (1.51 g).The mixture was warmed to ambient temperature for 30 minutes, heated atreflux for 5 hours, cooled, treated with 1N hydrochloric acid andconcentrated. The concentrate was partitioned between ethyl acetate andbrine, and the organic layer was washed with brine and water andconcentrated. The concentrate was purified by flash chromatography with50% ethyl acetate in hexane.

Example 1Btributyl(3-oxo-1,3,4,5,6,7-hexahydro-2-benzofuran-1-yl)phosphoniumbromide

A solution of EXAMPLE 1A (3 g) in acetic acid (10 mL) at ambienttemperature was treated with tri-n-butyl phosphine (4.81 mL) and 33%hydrobromic acid in acetic acid (3.34 mL), heated at reflux for 21hours, cooled and concentrated. The concentrate was purified by flashchromatography on silica gel with 10% methanol in dichloromethane.

Example 1C2-fluoro-5-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)benzonitrile

To a solution of EXAMPLE 1B (3.05 g) in dichloromethane (30 mL) wasadded 2-fluoro-5-formylbenzonitrile (1.08 g) and triethylamine (1.02mL). The mixture was stirred at ambient temperature for 16 hours andconcentrated. The concentrate was partitioned between ethyl acetate andbrine. The organic layer was washed with brine and concentrated. Theconcentrate was purified by flash chromatography on silica gel with 50%ethyl acetate in hexane.

Example 1D2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoicacid

To a suspension of EXAMPLE 1C (1.46 g) in water (15 mL) was added 50%sodium hydroxide. The mixture was heated at 90° C. for 1 hour. Aftercooling to 70° C., hydrazine monohydrate (0.54 mL) was added, and thesolution was stirred at 70° C. for 17 hours. The solution was cooled toambient temperature and brought to pH 4 with 6N hydrochloric acid. Theprecipitate was filtered, washed with water and dried. ¹H NMR (DMSO-d₆)δ1.55-1.69 (m, 4H), 2.31-2.42 (m, 4H), 3.93 (s, 2H), 7.24 (dd, J=10.8,8.5 Hz, 1H), 7.40-7.48 (m, 1H), 7.68 (dd, J=6.9, 2.2 Hz, 1H), 12.61 (s,1H), 13.22 (brs, 1H).

Example 24-(3-amino-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 2A3-(4-fluoro-3-nitrobenzylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

This example was prepared as described in EXAMPLE 1C by substituting4-fluoro-3-nitrobenzaldehyde for 2-fluoro-5-formylbenzonitrile.

Example 2B3-(3-amino-4-fluorobenzylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

A solution of EXAMPLE 2A (2.25 g) and ammonium chloride (0.83 g) inethanol (35 mL) and water (25 mL) at 70° C. was treated with iron powder(4.35 g), stirred for 3 hours and filtered through diatomaceous earth(CELITE®, World Minerals, Santa Barbara, Calif.) with hot ethanol. Thefiltrate was concentrated, and the concentrate was stirred with waterfor 30 minutes and filtered. The solid was washed with water and dried.

Example 2C4-(3-amino-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 2B (1.42 g) in ethanol (10 mL) was addedhydrazine monohydrate (0.27 mL). The mixture stirred at reflux for 1hour, cooled to 0° C., and filtered. The solid was washed with water anddried. ¹H NMR (CD₃OD) δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53(m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H),6.86 (dd, J=11.2, 8.1 Hz, 1H).

Example 34-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)amino)-4-oxobutanoicacid

To a solution of EXAMPLE 2 (872 mg) in acetonitrile was added succinicanhydride (370 mg). The mixture was heated at reflux for 17 hours,cooled and concentrated. The concentrate was purified by HPLC (Zorbax®C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.],0-100% acetonitrile/water with 0.1% trifluoroacetic acid). ¹H NMR(DMSO-d₆) δ1.53-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.55-2.67 (m, 2H),3.26-3.31 (m, 2H), 3.85 (s, 2H), 6.85-6.99 (m, 1H), 7.15 (dd, J=10.8,8.5 Hz, 1H), 7.74 (d, J=6.4 Hz, 1H), 9.70 (brs, 1H), 12.09 (brs, 1H),12.61 (s, 1H).

Example 41-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione

To EXAMPLE 3 (905 mg) in dichloromethane (30 mL) andN,N-dimethylformamide (6 mL) was added 1,1′-carbonyldiimidazole (785mg). The mixture was stirred at ambient temperature for 3 hours andconcentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0-100%acetonitrile/water with 0.1% trifluoroacetic acid). ¹H NMR (DMSO-d₆): δ1.57-1.69 (m, 4H), 2.32-2.42 (m, 4H), 2.78-2.89 (m, 4H), 3.93 (s, 2H),7.09-7.13 (m, 1H), 7.32-7.33 (m, 1H), 7.34 (d, J=1.2 Hz, 1H), 12.62 (s,1H).

Example 54-(3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 5A tert-butyl4-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepane-1-carboxylate

To EXAMPLE 1 (294 mg) in 1:1 N,N-dimethylformamide/pyridine (6 mL) wasadded 1,1′-carbonyldiimidazole (166 mg). The mixture was stirred atambient temperature for 30 minutes, and tert-butyl 1-homopiperazinecarboxylate (189 μL) was added. The mixture was stirred for 18 hours andconcentrated. The concentrate was purified by flash chromatography onsilica gel with 5% methanol in ethyl acetate.

Example 5B4-(3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 5A (330 mg) in dichloromethane (8 mL) at 0° C.was added trifluoroacetic acid (8 mL). The solution was warmed toambient temperature, and acetonitrile was added. The mixture wasconcentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0-100%acetonitrile/water with 0.1% trifluoroacetic acid). The product wasdissolved in methanol/dichloromethane and treated with 1M hydrochloricacid in diethyl ether and filtered to give the title compound as thehydrochloride salt. ¹H NMR (CD₃OD) δ 1.70-1.76 (m, 4H), 2.02-2.11 (m,2H), 2.52 (d, J=27.5 Hz, 4H), 3.32-3.36 (m, 2H), 3.40-3.46 (m, 2H), 3.51(t, J=6.1 Hz, 2H), 3.95-4.01 (m, 2H), 4.06 (s, 2H), 7.19 (t, J=9.0 Hz,1H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 1H).

Example 64-(3-(aminomethyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 6A

This example was prepared as described in EXAMPLE 2C by substitutingEXAMPLE 1C for EXAMPLE 2B.

Example 6B4-(3-(aminomethyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 6A (1.5 g) in 20% ammonia in methanol (150 mL)was added Raney nickel (15 g). The mixture was shaken under hydrogen (60psi) at ambient temperature for 2 hours, filtered, and concentrated. Theconcentrate was purified by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/waterwith 0.1% trifluoroacetic acid) to give the title compound as thetrifluoroacetate salt. ¹H NMR (CD₃OD) δ1.55-1.65 (m, 4H), 2.33-2.41 (m,4H), 3.90 (s, 2H), 4.04 (s, 2H), 7.21-7.25 (m, 1H), 7.27-7.29 (m, 1H),7.31 (d, J=7.0 Hz, 1H), 8.20-8.27 (brs, 2H).

Example 74-(3-((dimethylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 6 (75 mg) in methanol (8 mL) was added 37 wt %formaldehyde in water (39 μL) and triethylamine (36 μL). The solutionwas stirred at ambient temperature for 1 hour. Sodium cyanoborohydride(49 mg) and zinc chloride (35 mg) were added, and the mixture wasstirred for 60 hours and was concentrated. The concentrate was dissolvedin trifluoroacetic acidimethanol and purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0-100%acetonitrile/water with 0.1% trifluoroacetic acid). The product wasdissolved in methanol/dichloromethane and treated with 1M hydrochloricacid in diethyl ether to give the title compound as the hydrochloridesalt. ¹H NMR (CD₃OD) δ1.68-1.80 (m, 4H), 2.50-2.60 (m, 4H), 2.88 (s,6H), 4.10 (s, 2H), 4.39 (s, 2H), 7.22-7.27 (m, 1H), 7.40-7.44 (m, 1H),7.46 (dd, J=6.9, 2.0 Hz, 1H).

Example 84-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 7 by substituting acetone for formaldehyde. ¹H NMR (CD₃OD) δ1.39(d, J=6.7 Hz, 6H), 1.68-1.77 (m, 4H), 2.43-2.59 (m, 4H), 3.41-3.50 (m,1H), 4.05 (s, 2H), 4.24 (s, 2H), 7.18-7.24 (m, 1H), 7.35-7.38 (m, 1H),7.38-7.42 (m, 1H).

Example 94-(3-((cyclohexylamino)methyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 7 by substituting cyclohexanone for formaldehyde. ¹H NMR (CD₃OD)δ 1.32-1.46 (m, 4H), 1.68-1.81 (m, 6H), 1.84-1.94 (m, 2H), 2.13-2.22 (m,2H), 2.43-2.61 (m, 4H), 3.08-3.18 (m, 1H), 4.07 (s, 2H), 4.26 (s, 2H),7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.40-7.43 (m, 1H).

Example 104-(4-fluoro-3-((tetrahydro-2H-pyran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 7 by substituting tetrahydro-4H-pyran-4-one for formaldehyde. ¹HNMR (CD₃OD) δ 1.66-1.76 (m, 6H), 2.04-2.14 (m, 2H), 2.40-2.57 (m, 4H),3.40-3.51 (m, 3H), 4.03 (s, 2H), 4.05 (d, J=4.6 Hz, 2H), 4.29 (s, 2H),7.18-7.25 (m, 1H), 7.36-7.39 (m, 1H), 7.40 (d, J=1.8 Hz, 1H).

Example 114-(4-fluoro-3-((methyl((1-methylpyrrolidin-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 6 (75 mg) in methanol (8 mL) was added3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (104 mg) andtriethylamine (36 μL). The mixture was stirred at ambient temperaturefor 1 hour. Sodium cyanoborohydride (49 mg) and zinc chloride (35 mg)were added. The mixture was stirred for 60 hours and trifluoracetic acidwas added and the mixture stirred for one hour and was concentrated. Theconcentrate was dissolved in water/acetonitrile and was purified by HPLC(Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara,Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). Theresidue was treated as described above with 37 wt % formaldehyde inwater (39 μL), followed by treatment with 1M hydrochloric acid indiethyl ether to obtain the title compound as the HCl salt. ¹H NMR(CD₃OD) δ1.69-1.74 (m, 6H), 1.80-1.88 (m, 3H), 2.10-2.20 (m, 2H),2.44-2.58 (m, 6H), 3.10 (dd, J=11.4, 7.5 Hz, 2H), 3.22-3.26 (m, 1H),3.34-3.38 (m, 2H), 3.52-3.56 (m, 1H), 4.03 (s, 2H), 4.31 (s, 2H),7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.49 (dd, J=6.9, 2.0 Hz, 1H).

Example 124-(4-fluoro-3-((methyl(((2R)-1-methylpyrrolidin-2-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 11 by substituting N-(tert-butoxycarbonyl)-D-prolinal for3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. ¹H NMR (CD₃OD)δ 1.74-1.83 (m, 4H), 1.95-2.07 (m, 1H), 2.10-2.28 (m, 2H), 2.52-2.70 (m,5H), 2.91 (s, 3H), 3.04 (s, 3H), 3.21-3.29 (m, 1H), 3.63-3.69 (m, 1H),3.73-3.81 (m, 1H), 3.90-4.00 (m, 1H), 4.05-4.13 (m, 1H), 4.20 (s, 2H),4.50-4.62 (m, 2H), 7.27 (t, J=9.1 Hz, 1H), 7.44-7.49 (m, 1H), 7.64 (d,J=5.2 Hz, 1H).

Example 134-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 13A3-(3-(diethoxymethyl)benzylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

This example was prepared as described in EXAMPLE 1C by substituting3-(diethoxymethyl)benzaldehyde for 2-fluoro-5-formylbenzonitrile.

Example 13B4-(3-(diethoxymethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as described in EXAMPLE 2C by substitutingEXAMPLE 13A for EXAMPLE 2B.

Example 13C3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzaldehyde

To a solution of EXAMPLE 13B (681 mg) in a 1:1 mixture of ethanol/water(20 mL) was added concentrated sulfuric acid (0.4 mL). The mixture wasrefluxed for 16 hours. The mixture was cooled and concentrated, and theconcentrate was triturated with saturated sodium bicarbonate. The solidwas filtered, washed with water and dried.

Example 13D4-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 13C (80 mg) and cyclopropylamine (51 mg) inmethanol (8 mL) was stirred at ambient temperature for 1 hour. Sodiumcyanoborohydride (57 mg) was added, and the solution was stirred for 18hours and was concentrated. The concentrate was dissolved inmethanol/trifluoroacetic acid and was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0-100%acetonitrile/water with 0.1% trifluoroacetic acid). The product wasdissolved in methanol/dichloromethane and was treated with 1Mhydrochloric acid in diethyl ether and concentrated to give the titlecompound as the hydrochloride salt. ¹H NMR (CD₃OD) δ 0.82-0.92 (m, 4H),1.65-1.77 (m, 4H), 2.41-2.60 (m, 4H), 2.69-2.79 (m, 1H), 4.11 (s, 2H),4.28 (s, 2H), 7.31 (d, J=6.7 Hz, 1H), 7.34-7.40 (m, 2H), 7.41-7.45 (m,1H).

Example 144-(3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting isopropylamine for cyclopropylamine. ¹H NMR(CD₃OD) δ1.38 (d, J=6.7 Hz, 6H), 1.68-1.79 (m, 4H), 2.41-2.65 (m, 4H),3.38-3.48 (m, 1H), 4.12 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=7.1 Hz, 1H),7.35-7.38 (m, 1H), 7.38-7.41 (m, 1H), 7.41-7.46 (m, 1H).

Example 154-(3-(morpholin-4-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting morpholine for cyclopropylamine. ¹H NMR(CD₃OD) δ1.67-1.78 (m, 4H), 2.39-2.57 (m, 4H), 3.13-3.24 (m, 2H),3.32-3.39 (m, 2H), 3.71-3.80 (m, 2H), 4.03 (dd, J=13.3, 3.2 Hz, 2H),4.08 (s, 2H), 4.34 (s, 2H), 7.37 (d, J=6.7 Hz, 1H), 7.39-7.42 (m, 1H),7.41-7.44 (m, 1H), 7.44-7.48 (m, 1H).

Example 164-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting pyrrolidine for cyclopropylamine. ¹H NMR(CD₃OD) δ1.67-1.79 (m, 4H), 1.95-2.07 (m, 2H), 2.11-2.24 (m, 2H),2.44-2.65 (m, 4H), 3.09-3.26 (m, 2H), 3.41-3.54 (m, 2H), 4.15 (s, 2H),4.35 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.47 (m, 3H).

Example 174-(3-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting cyclohexylamine for cyclopropylamine. ¹H NMR(CD₃OD) δ1.20-1.27 (m, 1H), 1.31-1.45 (m, 4H), 1.66-1.78 (m, 5H),1.85-1.93 (m, 2H), 2.12-2.20 (m, 2H), 2.45-2.60 (m, 4H), 3.08 (dd,J=14.6, 7.6 Hz, 1H), 4.11 (s, 2H), 4.19 (s, 2H), 7.32 (d, J=7.0 Hz, 1H),7.34-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.41-7.45 (m, 1H).

Example 184-(3-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting 2M methylamine in methanol forcyclopropylamine. ¹H NMR (CD₃OD) δ1.69-1.78 (m, 4H), 2.45-2.59 (m, 4H),2.70 (s, 3H), 4.13 (s, 2H), 4.16 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.37(m, 1H), 7.37-7.40 (m, 1H), 7.43 (t, J=7.4 Hz, 1H).

Example 194-(3-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting 2-Methylamine in methanol forcyclopropylamine. ¹H NMR (CD₃OD) δ1.33 (t, J=7.2 Hz, 3H), 1.66-1.80 (m,4H), 2.42-2.62 (m, 4H), 3.10 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 4.16 (s,2H), 7.31 (d, J=7.1 Hz, 1H), 7.34-7.37 (m, 1H), 7.38-7.40 (m, 1H),7.41-7.45 (m, 1H).

Example 204-(3-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting 4-methylpiperidine for cyclopropylamine. ¹HNMR (CD₃OD) δ0.99 (d, J=6.4 Hz, 3H), 1.39-1.54 (m, 2H), 1.67-1.76 (m,5H), 1.83-1.95 (m, 2H), 2.44-2.63 (m, 4H), 2.92-3.04 (m, 2H), 3.35-3.46(m, 2H), 4.15 (s, 2H), 4.26 (s, 2H), 7.34-7.37 (m, 1H), 7.40-7.44 (m,2H), 7.44-7.47 (m, 1H).

Example 214-(3-(((2-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting 3-(trifluoromethyl)phenethylamine forcyclopropylamine. ¹H NMR (CD₃OD) δ1.64-1.72 (m, 4H), 2.40-2.57 (m, 4H),3.06-3.14 (m, 2H), 3.27-3.29 (m, 2H), 4.07 (s, 2H), 4.22 (s, 2H), 7.33(d, J=7.3 Hz, 1H), 7.35-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.44 (t, J=7.5Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.55-7.58 (m, 1H), 7.59 (d, J=5.2 Hz,1H), 7.60-7.62 (m, 1H).

Example 224-(3-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting N-methyl cyclohexylamine forcyclopropylamine. ¹H NMR (CD₃OD) δ1.23-1.40 (m, 3H), 1.53-1.65 (m, 2H),1.67-1.79 (m, 5H), 1.90-2.00 (m, 2H), 2.02-2.18 (m, 2H), 2.40-2.49 (m,2H), 2.49-2.58 (m, 2H), 2.71 (s, 3H), 3.16-3.28 (m, 1H), 4.07 (s, 2H),4.17 (d, J=12.9 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 7.34-7.36 (m, 1H),7.37-7.39 (m, 1H), 7.41 (s, 1H), 7.43-7.49 (m, 1H).

Example 234-(3-((2-ethylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13 by substituting 2-ethylpyrrolidine for cyclopropylamine. ¹HNMR (CD₃OD) δ0.94 (t, J=7.5 Hz, 3H), 1.52-1.63 (m, 1H), 1.69-1.77 (m,4H), 1.78-1.87 (m, 2H), 1.91-2.04 (m, 1H), 2.05-2.17 (m, 1H), 2.31-2.44(m, 1H), 2.45-2.64 (m, 4H), 3.19-3.28 (m, 1H), 3.34-3.47 (m, 2H), 4.15(s, 2H), 4.21 (d, J=12.9 Hz, 1H), 4.50 (d, J=13.2 Hz, 1H), 7.33-7.38 (m,1H), 7.40-7.44 (m, 2H), 7.44-7.48 (m, 1H).

Example 244-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 24A3-(4-(diethoxymethyl)benzylidene)-4,5,67-tetrahydroisobenzofuran-1(3H)-one

This example was prepared as described in EXAMPLE 1C by substituting4-(diethoxymethyl)benzaldehyde for 2-fluoro-5-formylbenzonitrile.

Example 24B4-(4-(diethoxymethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as described in EXAMPLE 2C by substitutingEXAMPLE 24A for EXAMPLE 2B.

Example 24C4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzaldehyde

This example was prepared as described in EXAMPLE 13C by substitutingEXAMPLE 24B for EXAMPLE 13B.

Example 24D4-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C. ¹H NMR (CD₃OD)δ0.82-0.88 (m, 2H), 0.89-0.94 (m, 2H), 1.62-1.77 (m, 4H), 2.35-2.44 (m,2H), 2.45-2.55 (m, 2H), 2.70-2.82 (m, 1H), 4.02 (s, 2H), 4.27 (s, 2H),7.30 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).

Example 254-(4-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and2-propylamine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.38 (d, J=6.4 Hz,6H), 1.65-1.72 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.52 (m, 2H), 3.39-3.50(m, 1H), 4.01 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.44 (d,J=8.0 Hz, 2H).

Example 264-(4-(morpholin-4-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and morpholinefor cyclopropylamine. ¹H NMR (CD₃OD) δ1.65-1.76 (m, 4H), 2.43-2.48 (m,2H), 2.49-2.58 (m, 2H), 3.13-3.24 (m, 2H), 3.33-3.37 (m, 2H), 3.36-3.41(m, 1H), 3.70-3.80 (m, 2H), 3.99-4.03 (m, 1H), 4.06 (s, 2H), 4.34 (s,2H), 7.35 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H).

Example 274-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and pyrrolidinefor cyclopropylamine. ¹H NMR (CD₃OD) δ1.63-1.76 (m, 4H), 1.94-2.06 (m,2H), 2.10-2.24 (m, 2H), 2.37-2.46 (m, 2H), 2.46-2.55 (m, 2H), 3.11-3.23(m, 2H), 3.38-3.58 (m, 2H), 4.02 (s, 2H), 4.34 (s, 2H), 7.33 (d, J=7.7Hz, 2H), 7.46 (d, J=8.0 Hz, 2H).

Example 284-(4-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C andcyclohexylamine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.21-1.29 (m, 1H),1.33-1.43 (m, 4H), 1.64-1.75 (m, 5H), 1.86-1.93 (m, 2H), 2.13-2.21 (m,2H), 2.37-2.44 (m, 2H), 2.49 (t, J=4.9 Hz, 2H), 3.05-3.16 (m, 1H), 4.01(s, 2H), 4.18 (s, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).

Example 294-(4-((4-phenylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and4-phenylpiperidine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.64-1.76 (m,4H), 1.93-2.03 (m, 2H), 2.05-2.15 (m, 2H), 2.40-2.49 (m, 2H), 2.48-2.55(m, 2H), 2.81-2.94 (m, 1H), 3.10-3.23 (m, 2H), 3.54-3.64 (m, 2H), 4.04(s, 2H), 4.33 (s, 2H), 7.19-7.22 (m, 1H), 7.24 (d, J=7.1 Hz, 2H),7.28-7.33 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.51 (d, J=7.7 Hz, 2H).

Example 304-(4-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and 2Mmethylamine in methanol for cyclopropylamine. ¹H NMR (CD₃OD) δ1.64-1.73(m, 4H), 2.38-2.44 (m, 2H), 2.47-2.54 (m, 2H), 2.71 (s, 3H), 4.02 (s,2H), 4.15 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).

Example 314-(4-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and2-Methylamine in methanol for cyclopropylamine. ¹H NMR (CD₃OD) δ61.32(t, J=7.4 Hz, 3H), 1.64-1.72 (m, 4H), 2.37-2.44 (m, 2H), 2.45-2.52 (m,2H), 3.10 (q, J=7.4 Hz, 2H), 4.01 (s, 2H), 4.15 (s, 2H), 7.30 (d, J=8.3Hz, 2H), 7.43 (d, J=8.0 Hz, 2H).

Example 324-(4-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and4-methylpiperidine for cyclopropylamine. ¹H NMR (CD₃OD) δ0.99 (d, J=6.4Hz, 3H), 1.33-1.48 (m, 2H), 1.66-1.75 (m, 5H), 1.85-1.95 (m, 2H),2.40-2.48 (m, 2H), 2.48-2.57 (m, 2H), 2.90-3.05 (m, 2H), 3.44 (d, J=12.3Hz, 2H), 4.04 (s, 2H), 4.25 (s, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d,J=8.0 Hz, 2H).

Example 334-(4-(((2-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and3-(trifluoromethyl)phenethylamine for cyclopropylamine. ¹H NMR (CD₃OD)δ1.62-1.72 (m, 4H), 2.38-2.44 (m, 2H), 2.46-2.52 (m, 2H), 3.06-3.14 (m,2H), 3.27-3.35 (m, 2H), 4.02 (s, 2H), 4.22 (s, 2H), 7.31 (d, J=8.3 Hz,2H), 7.45 (d, J=8.3 Hz, 2H), 7.53-7.57 (m, 2H), 7.57-7.62 (m, 2H).

Example 344-(4-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C andN-methylcyclohexylamine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.20-1.31(m, 1H), 1.32-1.44 (m, 2H), 1.54-1.63 (m, 2H), 1.65-1.75 (m, 5H),1.91-2.01 (m, 2H), 2.05-2.18 (m, 2H), 2.39-2.46 (m, 2H), 2.47-2.53 (m,2H), 2.71 (s, 3H), 3.23-3.29 (m, 1H), 4.03 (s, 2H), 4.13 (d, J=13.2 Hz,1H), 4.47 (d, J=13.2 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.43-7.46 (m, 2H).

Example 354-(4-((2-methylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and2-methylpyrrolidine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.39 (d, J=6.7Hz, 3H), 1.66-1.78 (m, 5H), 1.93-2.02 (m, 1H), 2.03-2.13 (m, 1H),2.29-2.38 (m, 1H), 2.39-2.45 (m, 2H), 2.47-2.53 (m, 2H), 3.15-3.27 (m,1H), 3.34-3.40 (m, 1H), 3.51-3.62 (m, 1H), 4.02 (s, 2H), 4.09-4.17 (m,1H), 4.43-4.55 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H).

Example 364-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting EXAMPLE 24C for EXAMPLE 13C and1-methylhomopiperazine for cyclopropylamine. ¹H NMR (CD₃OD) δ1.68-1.79(m, 4H), 2.29-2.42 (m, 2H), 2.46-2.53 (m, 2H), 2.53-2.62 (m, 2H), 2.97(s, 3H), 3.35-3.44 (m, 1H), 3.47-3.65 (m, 2H), 3.67-3.96 (m, 5H), 4.11(s, 2H), 4.46 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H).

Example 374-(3-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 13D by substituting 1-methylhomopiperazine for cyclopropylamine.¹H NMR (CD₃OD) δ1.68-1.81 (m, 4H), 2.29-2.41 (m, 2H), 2.44-2.53 (m, 2H),2.55-2.64 (m, 2H), 2.98 (s, 3H), 3.33-3.40 (m, 1H), 3.40-3.56 (m, 2H),3.58-3.72 (m, 1H), 3.73-3.97 (m, 4H), 4.15 (s, 2H), 4.46 (s, 2H), 7.37(d, J=7.7 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.51 (d, J=6.1 Hz, 2H).

Example 384-(4-fluoro-3-pyrimidin-2-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 38A3-(3-bromo-4-fluorobenzylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

This example was prepared as described in EXAMPLE 1C by substituting3-bromo-4-fluorobenzaldehyde for 2-fluoro-5-formylbenzonitrile.

Example 38B4-(3-bromo-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as described in EXAMPLE 2D by substitutingEXAMPLE 38A for EXAMPLE 2B.

Example 38C4-(4-fluoro-3-pyrimidin-2-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To EXAMPLE 38B (75 mg) in N,N-dimethylformamide (8 mL) was added2-tributylstannylpyrimidine (81 mg),tris(dibenzylidineacetone)dipalladium(0) (20 mg), tri-o-tolylphosphine(20 mg) and triethylamine (92 μL). The mixture was stirred at 70° C. for17 hours. After cooling, the mixture was filtered, and the filtrate wasconcentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0-100%acetonitrile/water with 0.1% trifluoroacetic acid). The product wasdissolved in methanol/dichloromethane and treated with 1M hydrochloricacid in diethyl ether and concentrated to provide the title compound asthe hydrochloride salt. ¹H NMR (CD₃OD) δ1.69-1.78 (m, 4H), 2.48-2.60 (m,4H), 4.11 (s, 2H), 7.27 (dd, J=10.8, 8.5 Hz, 1H), 7.43-7.50 (m, 1H),7.61 (t, J=5.1 Hz, 1H), 7.87 (dd, J=7.1, 2.4 Hz, 1H), 9.01 (d, J=5.1 Hz,2H).

Example 394-(4-fluoro-3-pyridin-3-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To EXAMPLE 38B (75 mg), 3-pyridineboronic acid (54 mg) anddichlorobis(triphenylphosphine)palladium (II) (28 mg) in 7:3:21,2-dimethoxyethane/water/ethanol (3 mL) was added 2M sodium carbonate(0.22 mL). The mixture was stirred in a CEM Explorer® microwave reactor(Matthews, N.C.) for 10 minutes at 150° C. After cooling, the mixturewas filtered, and the filtrate was concentrated. The concentrate waspurified by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1%trifluoroacetic acid). The product was dissolved inmethanol/dichloromethane and was treated with 1M hydrochloric acid indiethyl ether and concentrated to provide the title compound as thehydrochloride salt. ¹H NMR (CD₃OD) δ1.70-1.80 (m, 4H), 2.50-2.62 (m,4H), 4.17 (s, 2H), 7.33 (dd, J=10.7, 8.5 Hz, 1H), 7.40-7.48 (m, 1H),7.60 (dd, J=7.3, 1.8 Hz, 1H), 8.22 (dd, J=8.2, 5.8 Hz, 1H), 8.87 (d,J=8.2 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 9.12 (s, 1H).

Example 404-(4-fluoro-3-pyridin-4-ylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

This example was prepared as the hydrochloride salt as described inEXAMPLE 39 by substituting 4-pyridine boronic acid for 3-pyridineboronic acid. ¹H NMR (CD₃OD) δ1.68-1.84 (m, 4H), 2.46-2.64 (m, 4H), 4.15(s, 2H), 7.35 (dd, J=11.0, 8.5 Hz, 1H), 7.48-7.53 (m, 1H), 7.69 (dd,J=7.2, 2.0 Hz, 1H), 8.32 (d, J=5.8 Hz, 2H), 8.91 (d, J=6.7 Hz, 2H).

Example 41N,N-diethyl-2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-2-carboxamide

This example was prepared as the hydrochloride salt as described inEXAMPLE 39 by substituting (2-(N,N-diethylaminocarbonyl)phenyl)boronicacid for 3-pyridineboronic acid. ¹H NMR (CD₃OD) δ0.83 (t, J=7.2 Hz, 3H),0.93 (t, J=7.2 Hz, 3H), 1.72-1.83 (m, 4H), 2.51-2.66 (m, 4H), 2.73-3.01(m, 2H), 3.02-3.25 (m, 2H), 4.11 (s, 2H), 7.13-7.17 (m, 1H), 7.17-7.19(m, 1H), 7.26-7.31 (m, 1H), 7.38-7.41 (m, 2H), 7.47-7.50 (m, 1H),7.51-7.54 (m, 1H).

Example 42N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-piperidin-1-ylpropanamide

To 3-(1-piperidinyl)propionic acid (28 mg) in dichloromethane (3 mL) wasadded oxalyl chloride (24 μL) and a drop of N,N-dimethylformamide. Themixture was stirred at ambient temperature for 1 hour and concentrated.The concentrate was dissolved in dichloromethane (3 mL) and added to asolution of EXAMPLE 2C (50 mg) in tetrahydrofuran (3 mL). Triethylamine(31 μL) was also added. The mixture was stirred at ambient temperaturefor 16 hours and was concentrated. The concentrate was purified by HPLC(Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara,Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). Theproduct was dissolved in methanol/dichloromethane and treated with 1Mhydrochloric acid in diethyl ether and was concentrated to provide thetitle compound as the hydrochloride salt. ¹H NMR (CD₃OD) δ1.50-1.59 (m,1H), 1.68-1.75 (m, 4H), 1.76-1.87 (m, 3H), 1.92-2.01 (m, 2H), 2.41-2.57(m, 4H), 2.94-2.98 (m, 2H), 2.98-3.03 (m, 2H), 3.45 (t, J=6.9 Hz, 2H),3.57 (d, J=12.2 Hz, 2H), 3.99 (s, 2H), 6.99-7.05 (m, 1H), 7.11 (dd,J=10.4, 8.5 Hz, 1H), 7.81 (dd, J=7.3, 1.8 Hz, 1H).

Example 43N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide

This example was prepared as the hydrochloride salt as described inEXAMPLE 42 by substituting 3-(4-methylpiperazin-1-yl)propionic acid for3-(1-piperidinyl)propionic acid. ¹H NMR (CD₃OD) δ 1.65-1.79 (m, 4H),2.38-2.58 (m, 4H), 3.03 (s, 3H), 3.07 (t, J=6.7 Hz, 2H), 3.60-3.65 (m,2H), 3.65-3.68 (m, 3H), 3.70-3.89 (m, 4H), 3.97-4.06 (m, 1H), 4.00 (s,2H), 6.99-7.04 (m, 1H), 7.12 (dd, J=10.7, 8.5 Hz, 1H), 7.83 (dd, J=7.3,1.8 Hz, 1H).

Example 442-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

A solution of EXAMPLE 2 (50 mg) and Boc-L-glycine N-hydroxysuccinimideester (54 mg) in tetrahydrofuran (4 mL) was stirred at ambienttemperature for 16 hours and was concentrated. To this solid indichloromethane (2 mL) was added trifluoroacetic acid (1 mL) and themixture stirred at ambient temperature for 1 hour and concentrated. Theconcentrate was purified by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/waterwith 0.1% trifluoroacetic acid) to provide the title compound as thetrifluoroacetate salt. ¹H NMR (CD₃OD) δ 1.65-1.74 (m, 4H), 2.38-2.55 (m,4H), 3.89 (s, 2H), 3.96 (s, 2H), 7.00-7.06 (m, 1H), 7.09-7.16 (m, 1H),7.87 (dd, J=7.4, 2.1 Hz, 1H).

Example 453-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

This example was prepared as described in EXAMPLE 42 by substitutingcyclohexanepropionic acid for 3-(1-piperidinyl)propionic acid. ¹H NMR(CD₃OD) δ 0.90-1.00 (m, 2H) 1.16-1.33 (m, 4H) 1.53-1.61 (m, 2H)1.63-1.68 (m, 1H) 1.70-1.74 (m, 5H) 1.74-1.82 (m, 3H) 2.39-2.46 (m, 4H)2.48-2.51 (m, 2H) 3.94 (s, 2H) 6.96-7.01 (m, 1H) 7.07 (dd, J=10.7, 8.5Hz, 1H) 7.69 (dd, J=7.2, 1.7 Hz, 1H).

Example 46N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-3-carboxamide

This example was prepared as the trifluoroacetate salt as described inEXAMPLE 42 by substituting 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid for 3-(1-piperidinyl)propionic acid. ¹H NMR (CD₃OD) δ1.66-1.76 (m, 4H), 1.79-1.87 (m, 1H), 1.89-2.03 (m, 2H), 2.12 (dd,J=9.3, 4.9 Hz, 1H), 2.38-2.56 (m, 4H), 2.96-3.04 (m, 1H), 3.08-3.15 (m,1H), 3.17-3.25 (m, 2H), 3.33-3.35 (m, 1H), 3.95 (s, 2H), 6.99-7.06 (m,1H), 7.07-7.15 (m, 1H), 7.71 (dd, J=7.5, 2.0 Hz, 1H).

Example 474-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 2 (200 mg) in dichloromethane (5 mL) was added4-chlorobutanoylchloride (103 mg) and triethylamine (0.12 mL). Thesolution was stirred at ambient temperature for 16 hours and wasconcentrated. The concentrate was dissolved in ethanol (2 mL) and addedto a solution of 21 wt % sodium ethoxide in ethanol (0.47 mL). Themixture was stirred at ambient temperature for 16 hours, treated with 2Mhydrochloric acid (1 mL) and concentrated. The concentrate was purifiedby HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, SantaClara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroaceticacid). ¹H NMR (CD₃OD) δ 1.66-1.77 (m, 4H), 2.15-2.27 (m, 2H), 2.40-2.51(m, 4H), 2.51-2.58 (m, 2H), 3.78-3.86 (m, 2H), 3.97 (s, 2H), 7.11-7.15(m, 1H), 7.16-7.19 (m, 1H), 7.22-7.27 (m, 1H).

Example 48N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-3-carboxamide

This example was prepared as the trifluoroacetate salt as described inEXAMPLE 42 by substituting 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid for 3-(1-piperidinyl)propionic acid. ¹H NMR (CD₃OD) δ1.64-1.78 (m, 4H), 2.40-2.49 (m, 2H), 2.47-2.55 (m, 2H), 3.81-3.93 (m,1H), 3.96 (s, 2H), 4.20-4.33 (m, 4H), 6.99-7.06 (m, 1H), 7.07-7.15 (m,1H), 7.87 (dd, J=7.3, 2.2 Hz, 1H).

Example 49N-(2-(isopropylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamideExample 49A methyl3-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)benzoate

This example was prepared as described in EXAMPLE 1C by substitutingmethyl-3-formylbenzoate for 2-fluoro-5-formylbenzonitrile.

Example 49B3-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)benzoicacid

EXAMPLE 49A (6.09 g) in 1:1 tetrahydrofuran/water (60 mL) at ambienttemperature was treated with lithium hydroxide monohydrate (1.8 g) andstirred for 16 hours. The mixture was acidified with 2N hydrochloricacid and partitioned between ethyl acetate and brine. The organic layerwas washed with water and concentrated, and the concentrate was purifiedby flash chromatography on silica gel with ethyl acetate.

Example 49C3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoic acid

This example was prepared as described in EXAMPLE 2C by substitutingEXAMPLE 49B for EXAMPLE 2B.

Example 49DN-(2-(isopropylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

To a solution of EXAMPLE 49C (75 mg) in N,N-dimethylformamide (3 mL) wasadded N-isopropylethylenediamine (27 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg),1-hydroxybenzotriazole hydrate (35 mg) and triethylamine (0.11 mL). Themixture was stirred at ambient temperature for 16 hours and waspartitioned between brine and water. The organics were washed with brineand concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies. Santa Clara, Calif.], 0-100%acetonitrile/water with 0.10% trifluoroacetic acid) to provide the titlecompound as the trifluoroacetate salt. ¹H NMR (CD₃OD) δ 1.34 (d, J=6.7Hz, 6H), 1.65-1.74 (m, 4H), 2.37-2.44 (m, 2H), 2.47-2.54 (m, 2H), 3.23(t, J=5.9 Hz, 2H), 3.39-3.47 (m, 1H), 3.67 (t, J=5.9 Hz, 2H), 4.05 (s,2H), 7.41-7.44 (m, 2H), 7.71-7.74 (m, 2H).

Example 50N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-morpholin-4-ylacetamide

This example was prepared as the trifluoroacetate salt as described inEXAMPLE 41 by substituting morpholin-4-yl-acetic acid for3-(1-piperidinyl)propionic acid. ¹H NMR (CD₃OD) δ 1.65-1.73 (m, 4H),2.38-2.46 (m, 2H), 2.46-2.52 (m, 2H), 3.34-3.52 (m, 4H), 3.90-4.03 (m,6H), 4.19 (s, 2H), 7.03-7.09 (m, 1H), 7.10-7.17 (m, 1H), 7.85 (dd,J=7.3, 2.1 Hz, 1H).

Example 51N-(2-morpholin-4-ylethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamideExample 51A3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoic acid

The title compound was prepared according to procedure for EXAMPLE 1substituting 3-formylbenzonitrile for 2-fluoro-5-formylbenzonitrile inEXAMPLE 1C. MS (DCI/NH₄) m z 285 (M+H)⁺.

Example 51BN-(2-morpholin-4-ylethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

To a solution of EXAMPLE 51A (75 mg, 0.26 mmol) in anhydrousdichloromethane (5 mL) was added 4-(2-aminoethyl)morpholine (68 mg, 0.52mmol), benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (271 mg, 0.52 mmol), and N,N′-diisopropylethylamine(0.18 mmol, 1.04 mmol) under nitrogen. The reaction mixture was stirredat room temperature for 16 hours, and concentrated. The residue wasseparated by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 397 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.64-1.75 (m, 4H),2.37-2.45 (m, 2H), 2.45-2.55 (m, 2H), 3.15-3.27 (m, 2H), 3.40 (t, J=5.80Hz, 2H), 3.63-3.71 (m, 2H), 3.74-3.81 (m, 4H), 4.02-4.13 (m, 4H),7.42-7.46 (m, 2H), 7.71-7.75 (m, 2H).

Example 523-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting 1-(2-aminoethyl)pyrrolidine for4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 381 (M+H)⁺; ¹H NMR (500MHz, CD₃OD): δ 1.65-1.74 (m, 4H), 1.97-2.08 (m, 2H), 2.13-2.22 (m, 2H),2.39-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.10-3.20 (m, 2H), 3.42 (t, J=5.80Hz, 2H), 3.73 (t, J=5.95 Hz, 2H), 3.75-3.82 (m, 2H), 4.05 (s, 2H),7.42-7.46 (m, 2H), 7.70-7.74 (m, 2H).

Example 534-(3-((2-methylpyrrolidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting 2-methylpyrrolidine for4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 352 (M+H)⁺; ¹H NMR (500MHz, CD₃OD): δ 0.86 (d, J=6.41 Hz, 1H), 1.33 (d, J=6.41 Hz, 2H),1.60-1.67 (m, 2H), 1.70 (d, J=2.75 Hz, 3H), 1.73-1.80 (m, 1H), 1.90-1.99(m, 1H), 2.11-2.22 (m, 1H), 2.39-2.47 (m, 2H), 2.46-2.56 (m, 2H),3.43-3.51 (m, 1H), 3.57-3.67 (m, 1H), 4.02 (s, 2H), 4.21-4.28 (m, 1H),7.24-7.33 (m, 2H), 7.33-7.36 (m, 1H), 7.37-7.42 (m, 1H).

Example 54N-azepan-1-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting 1-aminohomopiperidine for4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 381 (M+H)⁺; ¹H NMR (500MHz, CD₃OD): δ 1.68-1.74 (m, 4H), 1.73-1.81 (m, 4H), 1.92-2.01 (m, 4H),2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 3.53-3.60 (m, 4H), 4.06 (s, 2H),7.45-7.50 (m, 2H), 7.70-7.73 (m, 2H).

Example 554-(3-(piperazin-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 55A tert-butyl4-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carboxylate

The title compound was prepared according to procedure for EXAMPLE 51substituting tert-butyl 1-piperazine carboxylate for4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 453 (M+H)⁺.

Example 55B4-(3-(piperazin-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 55A (480 mg, 1.76 mmol) in methylene chloride(10 mL) was added trifluoroacetic acid (5 mL). The solution was stirredat room temperature for 1 hour, and was concentrated. The residue waspurified by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 353 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.68-1.74 (m, 4H),2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.19-3.29 (m, 3H), 3.67-3.97 (m,5H), 4.04 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.36 (m, 1H), 7.36-7.39 (m,1H), 7.44 (t, J=7.48 Hz, 1H).

Example 56N-azetidin-3-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 55 substituting 3-amino-1-N-Boc-azetidine fortert-butyl 1-piperazine carboxylate. MS (DCI/NH₃) m/z 339 (M+H)⁺; ¹H NMR(500 MHz, CD₃OD): δ 1.63-1.76 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.55 (m,2H), 4.05 (s, 2H), 4.28-4.37 (m, 4H), 4.76-4.82 (m, 1H), 7.41-7.45 (m,2H), 7.69-7.74 (m, 2H).

Example 573-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-piperidin-3-ylbenzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 55 substituting(+/−)-3-amino-1-N-Boc-piperidine for tert-butyl 1-piperazinecarboxylate. MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ1.68-1.72 (m, 4H), 1.72-1.77 (m, 1H), 1.80-1.89 (m, 1H), 2.02-2.15 (m,2H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.85-3.00 (m, 2H), 3.33-3.39(m, 1H), 3.52 (dd, J=12.21, 4.27 Hz, 1H), 4.04 (s, 2H), 4.18-4.26 (m,1H), 7.40-7.43 (m, 2H), 7.66-7.71 (m, 2H).

Example 58N-(4-(dimethylamino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substitutingN,N-dimethyl-1,4-phenylenediamine for 4-(2-aminoethyl)morpholine. MS(DCI/NH₃) m/z 403 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.67-1.73 (m, 4H),2.42-2.48 (m, 2H), 2.47-2.55 (m, 2H), 3.28 (s, 6H), 4.08 (s, 2H),7.43-7.45 (m, 1H), 7.45-7.49 (m, 1H), 7.55 (d, J=8.85 Hz, 2H), 7.77-7.80(m, 1H), 7.79-7.82 (m, 1H), 7.89-7.93 (m, 2H).

Example 59N-(2-(4-methylpiperazin-1-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting2-(4-methyl-piperazin-1-yl)-ethylamine for 4-(2-aminoethyl)morpholine.MS (DCI/NH₃) m/z 410 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.67-1.73 (m,4H), 2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 2.82 (t, J=6.41 Hz, 2H), 2.87(s, 3H), 2.89-3.09 (m, 3H), 3.17-3.26 (m, 2H), 3.33-3.41 (m, 1H), 3.57(t, J=6.26 Hz, 2H), 4.04 (s, 2H), 4.72-4.83 (m, 2H), 7.39-7.44 (m, 2H),7.63-7.66 (m, 1H), 7.66-7.69 (m, 1H).

Example 604-(3-((4-(isoxazol-5-ylcarbonyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of isoxazole-5-carboxylic acid (32 mg, 0.28 mmol) in amixture of anhydrous N,N-dimethylformamide (2 mL) and pyridine (2 mL)was treated with 1,1′-carbonyldiimidazole (48 mg, 0.30 mmol) at 40° C.for 2 hours. EXAMPLE 55 (50 mg, 0.14 mmol) was added and the reactionmixture was heated at 60° C. for 3 hours. After cooling, the reactionmixture was concentrated on a rotary evaporator and the residue waspurified by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 448 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.65-1.76 (m, 4H),2.41-2.47 (m, 2H), 2.48-2.56 (m, 2H), 3.51-3.66 (m, 3H), 3.66-3.79 (m,3H), 3.79-3.94 (m, 2H), 4.04 (s, 2H), 7.27-7.30 (m, 1H), 7.32-7.35 (m,1H), 7.36-7.39 (m, 1H), 7.43 (t, J=7.48 Hz, 1H), 7.61-7.66 (m, 1H),7.86-7.91 (m, 1H).

Example 614-(3-((4-phenylpiperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting 4-phenylpiperidine for4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 428 (M+H)⁺; ¹H NMR (500MHz, CD₃OD): δ 1.54-1.65 (m, 1H), 1.64-1.71 (m, 4H), 1.72-1.82 (m, 2H),1.91-1.99 (m, 1H), 2.40-2.45 (m, 2H), 2.49-2.51 (m, 2H), 2.80-2.89 (m,1H), 2.89-2.98 (m, 1H), 3.15-3.26 (m, 1H), 3.71-3.82 (m, 1H), 4.04 (s,2H), 4.72-4.81 (m, 1H), 7.16-7.20 (m, 1H), 7.22-7.26 (m, 3H), 7.27-7.30(m, 2H), 7.30-7.32 (m, 1H), 7.34 (d, J=7.93 Hz, 1H), 7.42 (t, J=7.63 Hz,1H).

Example 623-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(piperidin-2-ylmethyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 55 substituting tert-butyl2-(aminomethyl)piperidine-1-carboxylate for tert-butyl 1-piperazinecarboxylate. MS (DCI/NH₃) m/z 381 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD):δ1.46-1.56 (m, 2H), 1.60-1.78 (m, 6H), 1.79-1.93 (m, 2H), 2.38-2.47 (m,2H), 2.47-2.55 (m, 2H), 3.14 (dd, J=13.27, 4.42 Hz, 2H), 3.46-3.52 (m,1H), 3.55-3.64 (m, 1H), 4.04 (s, 2H), 4.91-5.05 (m, 1H), 7.27-7.32 (m,1H), 7.35-7.40 (m, 2H), 7.43 (t, J=7.48 Hz, 1H).

Example 633-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(piperidin-4-ylmethyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 55 substituting4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester fortert-butyl 1-piperazine carboxylate. MS (DCI/NH₃) m/z 381 (M+H)⁺; ¹H NMR(500 MHz, CD₃OD): δ 1.40-1.52 (m, 2H), 1.64-1.74 (m, 4H), 1.91-2.03 (m,3H), 2.37-2.47 (m, 2H), 2.47-2.55 (m, 2H), 2.93-3.02 (m, 2H), 3.32-3.36(m, 2H), 3.37-3.44 (m, 2H), 4.04 (s, 2H), 7.38-7.43 (m, 2H), 7.65-7.69(m, 2H).

Example 643-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-piperidin-1-ylethyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 51 substituting 2-(piperidin-1-yl)ethanaminefor 4-(2-aminoethyl)morpholine. MS (DCI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (500MHz, CD₃OD): δ 1.50-1.58 (m, 1H), 1.67-1.73 (m, 4H), 1.76-1.88 (m, 3H),1.97 (d, J=14.34 Hz, 2H), 2.38-2.47 (m, 2H), 2.46-2.54 (m, 2H),2.93-3.04 (m, 2H), 3.32-3.37 (m, 2H), 3.68 (d, J=12.21 Hz, 2H), 3.74 (t,J=6.10 Hz, 2H), 4.05 (s, 2H), 7.42-7.45 (m, 2H), 7.70-7.74 (m, 2H).

Example 65N-(1-methylazetidin-3-yl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

To a solution of EXAMPLE 56 (25 mg, 0.07 mmol) in methanol (2 mL) wasadded formaldehyde (37% in water, 16 μL, 0.21 mmol) and triethylamine(10 μL, 0.07 mmol). The mixture was stirred at room temperature for 2hours before sodium cyanoborohydride (13 mg, 0.21 mmol) and zincchloride (10 mg) were added. The reaction mixture was stirred at roomtemperature for 16 hours, and concentrated. The residue was dissolved in1:1 mixture of acetonitrile and water, and purified by HPLC (Zorbax®C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.],0.1% trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as atrifluoroacetic acid salt. MS (DCI/NH₃) m/z 353 (M+H)⁺; ¹H NMR (500 MHz,CD₃OD): δ 1.63-1.74 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.01(d, J=17.70 Hz, 3H), 4.06 (d, J=10.68 Hz, 2H), 4.21-4.28 (m, 1H), 4.31(dd, J=11.44, 8.70 Hz, 1H), 4.56-4.66 (m, 2H), 5.51 (s, 1H), 7.41-7.44(m, 1H), 7.44-7.48 (m, 1H), 7.70-7.78 (m, 2H).

Example 66 methyl4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylateExample 66A3-((2-bromopyridin-4-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 2-bromo-pyridine-4-carbaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 307 (M+H)⁺.

Example 66B4-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C substituting EXAMPLE 66A for EXAMPLE 2B. MS (DCI/NH₃) m/z 321 (M+H)⁺.

Example 66C methyl4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate

A mixture of EXAMPLE 66B (800 mg, 2.5 mmol),dichloro(1,1′-ferrocenylbis(diphenyl-phosphine))palladium(II)dichloromethane (125 mg, 0.15 mmol) and triethylamine (1 ml) in amixture of methanol (40 ml) and N,N-dimethylformamide (16 ml) was heatedat 110° C. in a pressure vessel under 30 psi of carbon monoxide for 16hours. After cooling, the solid material was filtered off, and thefiltrate was concentrated. The residual solid was washed with methanol,and dried to provide the title compound. MS (DCI/NH₃) m/z 300 (M+H)⁺.

Example 67N-methyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

A solution of EXAMPLE 66 (100 mg, 0.33 mmol) in methanol (5 ml) wastreated with methylamine (2.0 N in methanol, 2 ml) at 50° C. for 24hours, and concentrated. The residue was washed with methanol, and driedto provide the title compound. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 684-((2-(methylthio)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 68A3-((2-(methylthio)pyrimidin-4-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 2-methylthio-4-pyrimidine-carboxyaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 275 (M+H)⁺.

Example 68B4-((2-(methylthio)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 68A for EXAMPLE 2B. MS (DCI/NH₃) m/z 289(M+H)⁺.

Example 694-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a suspension of EXAMPLE 68 (280 mg, 1 mmol) in methylene chloride (5mL) was added m-chloroperoxybenzoic acid (256 mg, 1.5 mmol). Thereaction mixture was stirred at room temperature for 4 hours, andconcentrated. The residual solid was separated by flash chromatographyon silica gel (80% ethyl acetate in hexane) to provide the titlecompound. MS (DCI/NH₃) m/z 321 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ1.61-1.89 (m, 4H), 2.37-2.71 (m, 4H), 3.32 (s, 3H), 4.29 (s, 2H), 7.65(d, J=5.09 Hz, 1H), 8.88 (d, J=5.43 Hz, 1H).

Example 704-((2-(methylsulfinyl)pyrimidin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was isolated as a side product in EXAMPLE 69. MS(ESI) m/z 305 (M+H)⁺.

Example 714-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 71A3-((3-bromopyridin-1-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 3-bromoisonicotinaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 306 (M+H)⁺.

Example 71B4-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 71A for EXAMPLE 2B. MS (DCI/NH₃) m/z 321(M+H)⁺.

Example 724-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 72A3-((6-bromopyridin-3-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 6-bromonicotinaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 306 (M+H)⁺.

Example 72B4-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 72A for EXAMPLE 2B. MS (DCI/NH₃) m/z 321(M+H)⁺.

Example 734-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 73A3-((2-bromopyridin-3-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 2-bromonicotinaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 306 (M+H)⁺.

Example 73B4-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 72A for EXAMPLE 2B. MS (DCI/NH₃) m/z 321(M+H)⁺.

Example 74 methyl6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylateExample 74A3-((6-bromopyridin-2-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 6-bromo-pyridine-2-carbaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 300 (M+H)⁺.

Example 74B4-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 74A for EXAMPLE 2B. MS (DCI/NH₃) m/z 321(M+H)⁺.

Example 74C methyl6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)picolinate

The title compound was prepared according to the procedure for EXAMPLE66C, substituting EXAMPLE 74B for EXAMPLE 66B. MS (DCI/NH₃) m/z 300(M+H)⁺.

Example 75N-ethyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting ethylamine for methylamine. MS (ESI) m/z 313 (M+H)⁺.

Example 76N-isopropyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting isopropyl amine for methyl amine. MS (ESI) m/z 327 (M+H)⁺.

Example 77N-cyclohexyl-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting cyclohexanamine for methyl amine. MS (ESI) m/z 367 (M+H)⁺;¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ 1.23-1.45 (m, 6H), 1.60-1.64(m, 4H), 1.65-1.86 (m, 5H), 2.30-2.40 (m, 4H), 4.03 (s, 2H), 7.41 (dd,J=4.92, 1.86 Hz, 1H), 7.86 (s, 1H), 8.41 (d, J=8.82 Hz, 1H), 8.53 (d,J=5.09 Hz, 1H), 12.64 (s, 1H).

Example 78N-methyl-N-((1-methylpiperidin-2-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 62 for EXAMPLE 56. MS(DCI/NH₃) m/z 409 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.47-1.57 (m, 1H),1.58-1.67 (m, 1H), 1.67-1.77 (m, 6H), 1.77-1.87 (m, 1H), 1.85-1.95 (m,1H), 2.43-2.51 (m, 2H), 2.53-2.63 (m, 2H), 2.99 (s, 3H), 3.08 (s, 3H),3.26 (dd, J=13.73, 3.36 Hz, 2H), 3.51-3.61 (m, 1H), 3.95 (dd, J=13.27,11.44 Hz, 1H), 4.13 (s, 2H), 5.11-5.24 (m, 1H), 7.35-7.40 (m, 2H),7.41-7.47 (m, 2H).

Example 79N-((1-methylpiperidin-4-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 63 for EXAMPLE 56. MS(DCI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD): δ 1.49-1.61 (m, 2H),1.69-1.78 (m, 4H), 1.90-1.98 (m, 1H), 1.97-2.08 (m, 2H), 2.43-2.53 (m,2H), 2.54-2.65 (m, 2H), 2.85 (s, 3H), 2.95-3.04 (m, 2H), 3.32-3.38 (m,2H), 3.53 (dd, J=10.53, 1.98 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H),7.43 (t, J=7.63 Hz, 1H), 7.68 (s, 1H), 7.70-7.73 (m, 1H).

Example 80N-methyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 74 for EXAMPLE 66. MS (ESI) m/z 299 (M+H)⁺; ¹H NMR(300 MHz, CD₃OD): δ 1.61-1.81 (m, 4H), 2.38-2.61 (m, 4H), 2.95 (s, 3H),4.22 (s, 2H), 7.41 (dd, J=7.46, 1.36 Hz, 1H), 7.88 (t, J=7.63 Hz, 1H),7.91-7.98 (m, 1H).

Example 81N-ethyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 74 for EXAMPLE 66, and ethylamine for methylamine.MS (ESI) m/z 313 (M+H)⁺.

Example 82N-isopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 74 for EXAMPLE 66, and isopropylamine formethylamine. MS (ESI) m/z 327 (M+H)⁺.

Example 83N-cyclopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 74 for EXAMPLE 66, and cyclopropylamine formethylamine. MS (ESI) m/z 325 (M+H)⁺.

Example 84N-cyclohexyl-6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 74 for EXAMPLE 66, and cyclohexylamine formethylamine. MS (ESI) m/z 367 (M+H)⁺.

Example 85 methyl3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate

The title compound was prepared according to procedure for EXAMPLE 66C,substituting EXAMPLE 73B for EXAMPLE 66B. MS (DCI/NH₃) m/z 300 (M+H)⁺.

Example 86 methyl5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxylate

The title compound was prepared according to the procedure for EXAMPLE66C, substituting EXAMPLE 72B for EXAMPLE 66B. MS (DCI/NH₃) m/z 300(M+H)⁺.

Example 874-((5-bromothiophen-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 87A3-((5-bromothiophen-2-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to procedure for EXAMPLE 1C,substituting 5-bromothiophene-2-carbaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 312 (M+H)⁺.

Example 87B4-((5-bromothiophen-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 87A for EXAMPLE 2B. MS (DCI/NH₃) m/z 326(M+H)⁺.

Example 884-((3-bromothiophen-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 88A3-((3-bromothiophen-2-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to procedure for EXAMPLE 1C,substituting 3-bromothiophene-2-carbaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 312 (M+H)⁺.

Example 88B4-((3-bromothiophen-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C substituting EXAMPLE 88A for EXAMPLE 2B. MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 89 4-(3-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2, substituting 3-nitrobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde inEXAMPLE 2A. MS (DCI/NH₃) m/z 256 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ1.62-1.75 (m, 4H), 2.37-2.44 (m, 2H), 2.46-2.54 (m, 2H), 3.86 (s, 2H),6.46-6.54 (m, 2H), 6.57 (dd, J=7.93, 1.98 Hz, 1H), 7.01 (t, J=7.73 Hz,1H).

Example 90 4-(3-bromobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C. substituting 3-bromobenzaldehyde for 4-fluoro-3-nitrobenzaldehyde.MS (DCI/NH₃) m/z 256 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ 1.64-1.77 (m,4H), 2.37-2.46 (m, 2H), 2.47-2.55 (m, 2H), 3.96 (s, 2H), 7.13-7.18 (m,1H), 7.18-7.24 (m, 1H), 7.35-7.40 (m, 2H).

Example 91 4-(thien-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A mixture of EXAMPLE 87 (100 mg, 0.31 mmol) and acetamide (1 g) wasstirred at 180° C. overnight. After cooling, the mixture was dissolvedin methanol, and separated by HPLC (Zorbax® C-8 packing material[Agilent Technologies, Santa Clara, Calif.]0.1% trifluoroaceticacid/CH₃CN/H₂O) to provide the title compound. MS (DCI/NH₃) m/z 247(M+H)⁺.

Example 92 methyl5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-2-carboxylate

The title compound was prepared according to the procedure for EXAMPLE66C, substituting EXAMPLE 87 for EXAMPLE 66B. MS (DCI/NH₃) m/z 305(M+H)⁺.

Example 93N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 86 for 66. MS (ESI) m/z 299 (M+H)⁺, ¹H NMR (300MHz, dimethylsulfoxide-d₆): δ 1.51-1.73 (m, 4H), 2.40 (d, J=14.92 Hz,4H), 2.81 (d, J=5.09 Hz, 3H), 4.02 (s, 2H), 7.75 (dd, J=7.97, 2.20 Hz,1H), 7.96 (d, J=8.14 Hz, 1H), 8.49 (d, 11.70 Hz, 1H), 8.70 (d, J=4.75Hz, 1H), 12.60 (s, 1H).

Example 94N-ethyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 86 for EXAMPLE 66, and ethylamine for methylamine.MS (ESI) m/z 313 (M+H)⁺.

Example 95N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 85 for 66. MS (ESI) m/z 299 (M+H)⁺, ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 1.53-1.79 (m, 4H), 2.29-2.44 (m, 4H), 2.73(d, J=5.16 Hz, 3H), 4.35 (s, 2H), 7.50 (dd, J=7.73, 4.56 Hz, 1H), 7.66(dd, J=7.93, 1.59 Hz, 1H), 8.49 (dd, J=4.36, 1.59 Hz, 1H), 8.65 (d,J=5.16 Hz, 1H), 12.35 (s, 1H).

Example 96N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridine-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 85 for EXAMPLE 66, and ethylamine for methylamine.MS (ESI) m/z 313 (M+H)⁺.

Example 97N,N-dimethyl-N′-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)sulfamide

To a solution of EXAMPLE 89 (50 mg, 02 mmol) in dichloromethane (4 mL)was added dimethylsulfamoyl chloride (31 mg, 0.22 mmol) and pyridine (17mL, 0.22 mol). The solution was stirred at room temperature for 16hours, and was concentrated. The residue was separated by HPLC (Zorbax®C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.],0.1% trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as atrifluoroacetic acid salt. MS (DCI/NH₃) m/z 363 (M+H)⁺; ¹H NMR (400 MHz,CD₃OD): δ 1.64-1.76 (m, 4H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.72(s, 6H), 3.95 (s, 2H), 6.91-6.96 (m, 1H), 7.02-7.06 (m, 2H), 7.19-7.24(m, 1H).

Example 98N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-piperidin-1-ylpropanamide

To a solution of 3-(piperidin-1-yl)propanoic acid (31 mg) in anhydrousdichloromethane (2 mL) was added oxalyl chloride (25.7 μL) and a drop ofN,N-dimethylformamide. The solution was stirred for 1 hour, and wasconcentrated. The residue was re-dissolved in anhydrous dichloromethane(2 mL), and was quickly added to a solution of EXAMPLE 89 (50 mg) inanhydrous tetrahydrofuran (2 mL). Triethylamine (32.8 μL) was added, andthe reaction mixture was stirred at room temperature overnight. Themixture was concentrated. The residue was partitioned between ethylacetate and brine. The organic phase was washed with brine andconcentrated. The residual solid was separated on HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as atrifluoroacetic acid salt. MS (DCI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (400 MHz,CD₃OD): δ 1.48-1.60 (m, 1H), 1.65-1.71 (m, 4H), 1.73-1.87 (m, 3H),1.92-2.01 (m, 2H), 2.38-2.45 (m, 2H), 2.46-2.53 (m, 2H), 2.87 (t, J=6.60Hz, 2H), 2.93-3.03 (m, 2H), 3.44 (t, J=6.75 Hz, 2H), 3.57 (d, J=12.58Hz, 2H), 3.97 (s, 2H), 6.95-7.00 (m, 1H), 7.26 (t, J=7.83 Hz, 1H),7.36-7.39 (m, 1H), 7.41-7.48 (m, 1H).

Example 994-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylbutanamide

A solution of EXAMPLE 89 (150 mg, 0.59 mmol) and 4-chlorobutanoylchloride (83 mg, 0.59 mmol) in dichloromethane (5 mL) was stirred atroom temperature for 16 hours, and was concentrated. The residue waspartitioned between ethyl acetate and brine. The organic phase waswashed with brine, and concentrated to provide the title compound. MS(DCI/NH₃) m/z 360 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD): δ 1.66-1.73 (m, 4H),2.07-2.15 (m, 2H), 2.40-2.46 (m, 2H), 2.48-2.51 (m, 2H), 2.50-2.56 (m,2H), 3.63 (t, J=6.44 Hz, 2H), 3.96 (s, 2H), 6.93 (d, J=7.67 Hz, 1H),7.21-7.26 (m, 1H), 7.36 (s, 1H), 7.38-7.46 (m, 1H).

Example 1004-(3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A suspension of EXAMPLE 90 (150 mg, 0.47 mmol), pyrrolidine-2-one (80mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.05mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (41 mg, 0.07 mmol) andcesium carbonate (214 mg, 0.66 mmol) in anhydrous dioxane (2 mL) washeated in a CEM Explorer® microwave reactor (Matthews, N.C.) at 200° C.for 30 minutes. After cooling, the reaction mixture was concentrated.The residue was separated by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies. Santa Clara, Calif.], 0.1% trifluoroaceticacid/CH₃CN/H₂O) to provide the title compound as a trifluoroacetic acidsalt. MS (DCI/NH₃) m/z 324 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD): δ 1.65-1.75(m, 4H), 2.11-2.23 (m, 2H), 2.41-2.47 (m, 2H), 2.48-2.53 (m, 2H), 2.57(t, J=7.98 Hz, 2H), 3.83-3.92 (m, 2H), 3.99 (s, 2H), 7.01 (d, J=7.67 Hz,1H), 7.31 (t, J=7.98 Hz, 1H), 7.38-7.42 (m, 1H), 7.51 (t, J=1.69 Hz,1H).

Example 1014-((2-(2-oxoazetidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A microwave tube was charged withtris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 0.006 mmol), Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (5.4 mg, 0.01 mmol),EXAMPLE 103 (50 mg, 0.16 mmol), azetidin-2-one (53 mg, 0.62 mmol) andCs₂CO₃ (70 mg, 0.21 mmol). Anhydrous dioxane was added, and thesuspension was heated in a CEM Explorer® microwave reactor (Matthews,N.C.) at 200° C. for 30 minutes. After concentration, the residue waspartitioned between ethyl acetate and brine. The organic phase wasconcentrated. The residual solid was separated by flash chromatographyon silica gel (100% ethyl acetate) to provide the title compound. MS(DCI/NH₃) m/z 311 (M+H)⁺.

Example 1024-((2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting pyrroline-2-one for azetidin-2-one. MS (ESI) m/z 339(M+H)⁺.

Example 1034-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as described in EXAMPLE 66B. MS(DCI/NH₃) m/z 321 (M+H)⁺.

Example 1044-((6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 72 for EXAMPLE 103, and pyrroline-2-one forazetidin-2-one. MS (ESI) m/z 325 (M+H)⁺.

Example 1054-((6-(2-oxoazetidin-1-yl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 72 for EXAMPLE 103. MS (ESI) m/z 311 (M+H)⁺.

Example 106N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)benzamide

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 72 for EXAMPLE 103, and benzamide forazetidin-2-one. MS (ESI) m/z 361 (M+H)⁺; ¹H NMR (300 MHz,dimethylsulfoxide-d₆): δ 1.48-1.70 (m, 4H), 2.41 (d, J=17.29 Hz, 4H),3.92 (s, 2H), 7.86 (t, J=1.86 Hz, 3H), 7.86-7.90 (m, 2H), 7.99-8.06 (m,1H), 8.12 (d, J=8.48 Hz, 1H), 8.24 (d, J=2.37 Hz, 1H), 10.72 (s, 1H)12.60 (s, 1H).

Example 107N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)isonicotinamide

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 72 for EXAMPLE 103, and isonicotinamide forazetidin-2-one. MS (ESI) m/z 362 (M+H)⁺; ¹H NMR (300 MHz,dimethylsulfoxide-d₆): δ 1.65 (d, J=5.09 Hz, 4H), 2.41 (d, J=16.28 Hz,4H), 3.93 (s, 2H), 7.68 (dd, J=8.48, 2.37 Hz, 1H), 7.90-8.00 (m, 2H),8.11 (d, J=8.48 Hz, 1H), 8.27 (d, J=2.03 Hz, 1H), 8.76-8.82 (m, 2H),11.12 (s, 1H), 12.60 (s, 1H).

Example 108N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)nicotinamide

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 72 for EXAMPLE 103, and nicotinamide forazetidin-2-one. MS (ESI) m/z 362 (M+H)⁺.

Example 1094-((5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,2′-bipyridin-5-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was a side-product of EXAMPLE 108. MS (ESI) m/z 481(M+H)⁺.

Example 110N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-2-carboxamide

The title compound was prepared according to procedure for EXAMPLE 67,substituting EXAMPLE 92 for 66. MS (ESI) m/z 304 (M+H)⁺; ¹H NMR (300MHz, dimethylsulfoxide-d₆): δ 1.63 (d, J=3.05 Hz, 4H), 2.29-2.46 (m,4H), 2.72 (d, J=—4.41 Hz, 3H), 4.09 (s, 2H), 6.88 (d, J=3.73 Hz, 1H),7.51 (d, J=3.73 Hz, 1H), 8.31 (d, J=4.41 Hz, I H), 12.66 (s, 1H).

Example 111N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)glycinamide

A solution of EXAMPLE 89 (50 mg, 0.2 mmol) and 2,5-dioxopyrrolidin-1-yl2-(tert-butoxycarbonylamino)acetate 59 mg, 0.22 mmol) in anhydroustetrahydrofuran (4 mL) was stirred at room temperature for 16 hours, andconcentrated. The residual solid was dissolved in dichloromethane (4 mL)and treated with trifluoroacetic acid (2 mL) at room temperature for 1hour. The reaction mixture was concentrated and the residue wasseparated by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 313 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ 1.64-1.75 (m, 4H),2.36-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.80 (s, 2H), 3.98 (s, 2H), 7.00(d, J=7.80 Hz, 1H), 7.28 (t, J=7.97 Hz, 1H), 7.37-7.40 (m, 1H),7.42-7.47 (m, 1H).

Example 112N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-2-carboxamideExample 112A tert-butyl2-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylcarbamoyl)azetidine-1-carboxylate

The title compound was prepared according to procedure for EXAMPLE 98,substituting 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid for3-(piperidin-1-yl)propanoic acid. MS (DCI/NH₃) m/z 439 (M+H)⁺.

Example 112BN-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-2-carboxamide

A solution of EXAMPLE 112A (64 mg) in dichloromethane (4 mL) was treatedwith trifluoroacetic acid (2 mL) at room temperature for 1 hour. Thereaction mixture was concentrated and the residue was purified by HPLC(Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara,Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O) to provide the titlecompound as a trifluoroacetic acid salt. MS (DCI/NH₃) m/z 339 (M+H)⁺; ¹HNMR (300 MHz, CD₃OD): δ 1.64-1.73 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.53(m, 2H), 2.57-2.69 (m, 1H), 2.81-2.93 (m, 1H), 3.94-4.04 (m, 1H), 3.98(s, 2H), 4.08-4.20 (m, 1H), 5.07 (dd, J=9.49, 7.80 Hz, 1H), 7.03 (d,J=8.14 Hz, 1H), 7.30 (t, J=7.80 Hz, 1H), 7.41 (t, —1.70 Hz, 1H), 7.49(dd, J=7.97, 1.53 Hz, 1H).

Example 113N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)azetidine-3-carboxamide

The title compound was prepared according to procedure for EXAMPLE 112,substituting 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid for1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid. MS (DCI/NH₃) m/z 339(M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ1.62-1.75 (m, 4H), 2.36-2.44 (m, 2H),2.46-2.54 (m, 2H), 3.69-3.83 (m, 1H), 3.97 (s, 2H), 4.17-4.33 (m, 4H),7.00 (dd, J=7.14, 1.19 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H), 7.40 (t, J=1.59Hz, 1H), 7.45-7.51 (m, 1H).

Example 114N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)methanesulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting methanesulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 334 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.53-1.67 (m, 4H), 2.29-2.42 (m, 4H), 2.95 (s,3H), 3.88 (s, 2H), 6.92 (d, J=7.63 Hz, 1H), 7.00 (s, 1H), 7.06 (dd,J=7.93, 1.22 Hz, 1H), 7.26 (t, J=7.78 Hz, 1H), 9.68 (br s, 1H), 12.63(br s, 1H).

Example 115N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propane-2-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting propane-2-sulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 362 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.19 (d, J=7.02 Hz, 6H), 1.53-1.66 (m, 4H),2.25-2.33 (m, 2H), 2.34-2.41 (m, 2H), 3.08-3.22 (m, 1H), 3.87 (s, 2H),6.88-6.91 (m, 1H), 7.01 (s, 1H), 7.08 (dd, J=8.24, 1.22 Hz, 1H), 7.23(t, J=7.78 Hz, 1H), 9.68 (br s, 1H), 12.64 (br s, 1H).

Example 116N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzenesulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting benzenesulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 396 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.48-1.60 (m, 4H), 2.10-2.21 (m, 2H), 2.29-2.39(m, 2H), 3.78 (s, 2H), 6.83-6.87 (m, 2H), 6.92 (dd, J=8.09, 1.37 Hz,1H), 7.15 (t, J=7.78 Hz, 1H), 7.48 (t, J=7.78 Hz, 2H), 7.58 (t, J=7.48Hz, 1H), 7.64-7.69 (m, 2H), 10.24 (br s, 1H), 12.64 (br s, 1H).

Example 117N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyridine-3-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting pyridine-3-sulfonyl chloride hydrochloride fordimethylsulfamoyl chloride. MS (DCI/NH₃) m/z 397 (M+H)⁺; ¹H NMR (500MHz, dimethylsulfoxide-d₆): δ 1.50-1.61 (m, 4H), 2.12-2.21 (m, 2H),2.33-2.40 (m, 2H), 3.80 (s, 2H), 6.85 (s, 1H), 6.92 (d, J=7.63 Hz, 1H),6.96 (dd, J=7.93, 1.22 Hz, 1H), 7.19 (t, J=7.78 Hz, 1H), 7.55 (dd,J=8.09, 4.73 Hz, 1H), 8.02-8.06 (m, 1H), 8.75 (dd, J=4.88, 1.53 Hz, 1H),8.77 (d, J=1.83 Hz, 1H), 10.43 (br s, 1H), 12.63 (br s, 1H).

Example 118N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)furan-2-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting furan-2-sulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 386 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.52-1.63 (m, 4H), 2.19-2.28 (m, 2H), 2.32-2.40(m, 2H), 3.82 (s, 2H), 6.57 (dd, J=3.66, 1.83 Hz, 1H), 6.89 (d, J=1.53Hz, 1H), 6.91 (d, J=7.63 Hz, 1H), 6.95-6.99 (m, 1H), 7.04 (d, J=3.36 Hz,1H), 7.20 (t, J=7.78 Hz, 1H), 7.90 (dd, J=1.83, 0.92 Hz, 1H), 10.60 (brs, 1H), 12.65 (br s, 1H).

Example 1191-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-imidazole-4-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting 1-methyl-1H-imidazole-4-sulfonyl chloride fordimethylsulfamoyl chloride. MS (DCI/CH₃) m/z 400 (M+H)⁺. ¹H NMR (500MHz, dimethylsulfoxide-d₆): δ 1.55-1.61 (m, 4H), 2.24-2.32 (m, 2H),2.32-2.40 (m, 2H), 3.63 (s, 3H), 3.80 (s, 2H), 6.80 (d, J=7.93 Hz, 1H),6.92 (s, 1H), 6.99 (dd, J=8.09, 1.37 Hz, 1H), 7.13 (t, J=7.78 Hz, 1H),7.70 (d, J=1.22 Hz, 1H), 7.73 (d, J=1.22 Hz, 1H), 10.15 (br s, 1H),12.64 (br s, 1H).

Example 120N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting thiophene-2-sulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.41-1.64 (m, 4H), 2.18-2.24 (m, 2H), 2.34-2.40(m, 2H), 3.82 (s, 2H), 6.90-6.94 (m, 2H), 6.97 (d, J=7.93 Hz, 1H), 7.06(dd, J=5.03, 3.81 Hz, 1H), 7.17-7.24 (m, 1H), 7.45 (dd, J=3.81, 1.37 Hz,1H), 7.85 (dd, J=5.03, 1.37 Hz, 1H), 10.36 (br s, 1H), 12.65 (br s, 1H).

Example 1214-cyano-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzenesulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting 4-cyanobenzene-1-sulfonyl chloride fordimethylsulfamoyl chloride. MS (DCI/NH₃) m/z 421 (M+H)⁺; ¹H NMR (500MHz, dimethylsulfoxide-d₆): δ 1.49-1.62 (m, 4H), 2.14-2.20 (m, 2H),2.31-2.39 (m, 2H), 3.80 (s, 2H), 6.84 (s, 1H), 6.90 (d, J=7.63 Hz, 1H),6.94 (dd, J=7.93, 1.22 Hz, 1H), 7.19 (t, J=7.93 Hz, 1H), 7.83 (d, J=8.85Hz, 2H), 8.00 (d, J=8.54 Hz, 2H), 10.52 (br s, 1H), 12.65 (br s, 1H).

Example 122N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)naphthalene-1-sulfonamide

The title compound was prepared according to the procedure for EXAMPLE97, substituting naphthalene-1-sulfonyl chloride for dimethylsulfamoylchloride. MS (DCI/NH₃) m/z 421 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d): δ 1.41-1.47 (m, 2H), 1.47-1.56 (m, 2H), 2.00-2.10(m, 2H), 2.30-2.39 (m, 2H), 3.71 (s, 2H), 6.75-6.80 (m, 2H), 6.83-6.89(m, 1H), 7.07 (t, J=7.78 Hz, 1H), 7.50-7.56 (m, 1H), 7.64 (t, J=7.02 Hz,1H), 7.67-7.72 (m, 1H), 8.04 (d, J=7.63 Hz, 1H), 8.06-8.10 (m, 1H), 8.18(d, J=8.24 Hz, 1H), 8.67 (d, J=8.54 Hz, 1H), 10.65 (br s, 1H), 12.64 (brs, 1H).

Example 1234-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as described in EXAMPLE 74B. MS(DCI/NH₃) m/z 321 (M+H)⁺.

Example 1254-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 123 for EXAMPLE 103, and pyrroline-2-one forazetidin-2-one. MS (ESI) m/z 325 (M+H)⁺.

Example 126N-(6-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)pyridin-2-yl)benzamide

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 123 for EXAMPLE 103, and benzylamide forazetidin-2-one. MS (ESI) m/z 361 (M+H)⁺; ¹H NMR (300 MHz,dimethylsulfoxide-d): δ 1.63 (m, 4H), 2.40 (m, 4H), 4.02 (s, 2H), 6.95(d, J=7.46 Hz, 1H), 7.38-7.54 (m, 2H), 7.50-7.62 (m, 1H), 7.67-7.84 (m,1H), 7.90-8.12 (m, 3H), 10.69 (s, 1H), 12.61 (s, 1H).

Example 1274-((3′-((isopropylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 127A3′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)biphenyl-3-carbaldehyde

A suspension of EXAMPLE 90 (500 mg, 1.57 mmol), 3-formylphenylboronicacid (352 mg, 2.35 mmol), dichlorobis(triphenylphosphine)palladium(II)(112 mg, 0.16 mmol) and sodium carbonate (2M solution, 3.13 mmol, 1.6mL) in a 7/3/3 mixture of 1,2-dimethoxyethane/water/ethanol (23 mL) waspurged with nitrogen, and heated at 70° C. for 16 hours. After coolingto room temperature, the reaction mixture was concentrated on a rotaryevaporator. The crude solid was separated by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound. MS(DCI/NH₃) m/z 345 (M+H)⁺.

Example 127B4-((3′-((isopropylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde,and propan-2-amine for EXAMPLE 56. MS (DCI/NH₃) m/z 388 (M+H)⁺; ¹H NMR(500 MHz, CD₃OD): δ 1.41 (d, J=6.71 Hz, 6H), 1.64-1.76 (m, 4H),2.43-2.48 (m, 2H), 2.48-2.53 (m, 2H), 3.42-3.52 (m, 1H), 4.06 (s, 2H),4.27 (s, 2H), 7.22 (d, J=7.93 Hz, 1H), 7.41 (t, J=7.63 Hz, 1H),7.45-7.50 (m, 2H), 7.51-7.56 (m, 2H), 7.64-7.69 (m, 1H), 7.71-7.74 (m,1H).

Example 1284-((3′-((cyclopentylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde,and cyclopentanamine for EXAMPLE 56. MS (DCI/NH₃) m/z 414 (M+H)⁺.

Example 1294-((3′-((2-methylpyrrolidin-1-yl)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehydeand 2-methylpyrrolidine for EXAMPLE 56. MS (DCI/NH₃) m/z 414 (M+H)⁺.

Example 1304-((3′-((cyclopropylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde,and cyclopropanamine for EXAMPLE 56. MS (DCI/NH₃) m/z 386 (M+H)⁺.

Example 1314-((3′-((cyclobutylamino)methyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a trifluoroacetic acid salt accordingto procedure for EXAMPLE 65, substituting EXAMPLE 127A for formaldehyde,and cyclobutanamine for EXAMPLE 56. MS (DCI/NH₃) m/z 400 (M+H)⁺.

Example 1324-((2-bromo-1-oxidopyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 103 (100 mg, 0.31 mmol) in dichloromethane (15 ml)was treated with meta-chloroperoxybenzoic acid (100 mg, 0.58 mmol) atroom temperature overnight, and concentrated. The residue was dissolvedin methanol, and separated by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid,CH₃CN/H₂O) to provide the title compound as a trifluoroacetic acid salt.MS (DCI/NH₃) m/z 336 (M+H)⁺.

Example 1334-((1-oxido-2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 132,substituting EXAMPLE 102 for EXAMPLE 103. MS (ESI) m/z 341 (M+H)⁺.

Example 134 methyl5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-3-carboxylateExample 134A3-((4-bromothiophen-2-yl)methylene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 5-bromothiophene-2-carbaldehyde for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₄) m/z 312 (M+H)⁺.

Example 134B4-((4-bromothiophen-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C substituting EXAMPLE 134A for EXAMPLE 2B. MS (DCI/NH₃) m/z 326(M+H)⁺.

Example 134C methyl5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)thiophene-3-carboxylate

The title compound was prepared according to the procedure for EXAMPLE66, substituting EXAMPLE 134B for EXAMPLE 66B. MS (DCI/NH₃) m/z 305(M+H)⁺.

Example 1354-(3-((4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-oneExample 135A tert-butyl2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepan-1-yl)ethoxy)ethoxy)ethylcarbamate

To a solution of 2-(2-(-t-Boc-aminoethoxy)ethoxy)ethyl bromide (Toronto,137 mg, 0.44 mmol) in N,N-dimethylformamide (4 mL) was added EXAMPLE 5(84 mg, 0.22 mmol) and potassium carbonate (91 mg, 0.66 mmol). Thereaction mixture was heated at 35° C. overnight, and partitioned betweenethyl acetate and brine. The organic phase was washed with brine, andconcentrated. The residue was separated by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 250×2.54column, mobile phase A: 0.1% trifluoroacetic acid in H₂O: B: 0.1%trifluoroacetic acid in CH₃CN; 0-100% gradient) to provide the titlecompound as a trifluoroacetic acid salt. MS (DCI/NH₃) m/z 612 (M+H)⁺.

Example 135B4-(3-((4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a suspension of EXAMPLE 135A (43 mg, 0.06 mmol) in dichloromethane (5mL) was added trifluoroacetic acid (1 mL) at room temperature. Thesolution remained at room temperature for 1 hour, and was concentrated.The residue was purified by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies, Santa Clara, Calif.], 250×2.54 column, mobilephase A: 0.1% trifluoroacetic acid in H₂O; B: 0.1% trifluoroacetic acidin CH₃CN; 0-100% gradient) to provide the title compound as atrifluoroacetic acid salt. The trifluoroacetic acid salt was dissolvedin a mixture of methylene chloride and methanol, and was treated with 1Msolution of HCl in ether. Removal of the volatiles afforded the titlecompound as a HCl salt. MS (DCI/NH₃) m/z 338 (M+H)⁺.

Example 1361-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropanecarboxamide

A solution of EXAMPLE 89 (20 mg, 0.08 mmol),1-methylcyclopropanecarboxylic acid (10 mg, 0.096 mmol), HATU(2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium) (38 mg, 0.1 mmol) and triethylamine(20 mg, 0.2 mmol) in dimethylacetamide (2.5 mL) was stirred at roomtemperature for 18 hours, and concentrated. The residue was dissolved ina 1:1 mixture of dimethylsulfoxide/methanol, and separated by HPLC(Waters Sunfire® C-8 analytical column [Milford, Mass.], 0.1%trifluoroacetic acid/water/CH₃CN) to provide the title compound. MS(DCI/NH₃) m/z 338 (M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ0.57-0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H),2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.23 (t,J=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).

Example 1372-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropanecarboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-methylcyclopropanecarboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 338 (M+H)⁺.

Example 1383-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-ethoxypropanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 356 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ ¹H NMR (500 MHz, Solvent) δ 1.08(t, J=7.02 Hz, 3H), 1.54-1.64 (m, 4H), 2.32-2.42 (m, 4H), 2.51 (t,J=6.26 Hz, 2H), 3.43 (q, J=7.02 Hz, 2H), 3.64 (t, J=6.26 Hz, 2H), 3.88(s, 2H), 6.90 (d, J=7.63 Hz, 1H), 7.24 (t, 7.78 Hz, 1H), 7.36 (s, 1H),7.48 (d, J=7.93 Hz, 1H).

Example 1395-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-L-prolinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting (S)-5-oxopyrrolidine-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ ¹H NMR (500 MHz, Solvent) δ1.56-1.66 (m, 4H), 1.93-2.03 (m, 1H), 2.14-2.27 (m, 2H), 2.32-2.43 (m,5H), 3.96 (s, 2H), 4.19 (dd, J=8.70, 4.42 Hz, 1H), 6.94 (d, J=7.63 Hz,1H), 7.27 (t, J=7.93 Hz, 1H), 7.40 (s, 1H), 7.49 (d, J=7.93 Hz, 1H).

Example 1405-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-D-prolinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting (R)-5-oxopyrrolidine-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.56-1.66 (m, 4H), 1.93-2.02 (m,1H), 2.13-2.25 (m, 2H), 2.32-2.42 (m, 5H), 3.89 (s, 2H), 4.18 (dd,J=8.70, 4.42 Hz, 1H), 6.94 (d, J=7.63 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H),7.39 (s, 1H), 7.49 (d, J=8.24 Hz, 1H).

Example 141N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)cyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-carbamoylcyclopropanecarboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.35-1.44 (m, 4H), 1.55-1.67 (m,4H), 2.31-2.44 (m, 4H), 3.88 (s, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.26 (t,J=7.78 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J=7.93 Hz, 1H).

Example 1422-(benzyloxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(benzyloxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺. ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.56-1.64 (m, 4H), 2.32-2.42 (m,4H), 3.89 (s, 2H), 4.06 (s, 2H), 4.60 (s, 2H), 6.93 (d, J=7.63 Hz, 1H),7.26 (t, J=7.78 Hz, 1H), 7.31-7.34 (m, 1H), 7.36-7.42 (m, 5H), 7.50 (d,J=7.93 Hz, 1H).

Example 143N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-phenylpropanamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-phenylpropanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 388 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.65 (m, 4H), 2.32-2.42 (m,4H), 2.60 (t, J=7.63 Hz, 2H), 2.89 (t, J=7.63 Hz, 2H), 3.87 (s, 2H),6.89 (d, J=7.63 Hz, 1H), 7.18 (t, J=7.17 Hz, 1H), 7.21-7.26 (m, 3H),7.28 (t, J=7.48 Hz, 2H), 7.32 (s, 1H), 7.45 (d, J=8.24 Hz, 1H).

Example 1443-(2,5-dimethoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(2,5-dimethoxyphenyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 145N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-phenylcyclopropanecarboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-phenylcyclopropanecarboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 400 (M+H)⁺.

Example 146(2S)—N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylbutanamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting (S)-2-phenylbutanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 402 (M+H)⁺.

Example 147N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 4-phenylbutanoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 402 (M+H)⁺.

Example 1482-(3-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(m-tolyloxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 1492-(2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(o-tolyloxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 1502-(4-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-(p-tolyloxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.56-1.65 (m, 4H), 2.23 (s, 3H),2.33-2.44 (m, 4H), 3.89 (s, 2H), 4.61 (s, 2H), 6.88 (d, J=8.54 Hz, 2H),6.94 (d, J=7.63 Hz, 1H), 7.11 (d, J=8.24 Hz, 2H), 7.27 (t, J=7.78 Hz,1H), 7.41 (s, 1H), 7.50 (d, J=8.24 Hz, 1H).

Example 151(2R)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylacetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting (R)-2-methoxy-2-phenylacetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.53-1.66 (m, 4H), 2.29-2.44 (m,4H), 3.35 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d, J=7.63 Hz, 1H),7.25 (t, J=7.93 Hz, 1H), 7.33-7.36 (m, 1H), 7.39 (t, J=7.17 Hz, 2H),7.45-7.49 (m, 3H), 7.52 (d, J=8.24 Hz, 1H).

Example 152(2S)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylacetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting (S)-2-methoxy-2-phenylacetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.53-1.66 (m, 4H), 2.30-2.42 (m,4H), 3.34 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d, J=7.63 Hz, 1H),7.25 (t, J=7.93 Hz, 1H), 7.32-7.36 (m, 1H), 7.39 (t, J=7.17 Hz, 2H),7.44-7.49 (m, 3H), 7.51 (d, J=8.24 Hz, 1H).

Example 153N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-phenoxypropanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 154N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-thien-2-ylbutanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 4-(thiophen-2-yl)butanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m z 408 (M+H)⁺.

Example 1551-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-acetylpiperidine-4-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 409 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.36-1.46 (m, 1H), 1.52-1.67 (m,5H), 1.79 (t, J=14.19 Hz, 2H), 2.02 (s, 3H), 2.30-2.43 (m, 4H),2.56-2.63 (m, 1H), 3.06 (t, J=12.97 Hz, 1H), 3.85-3.90 (m, 2H), 3.97 (s,2H), 4.39 (d, J=13.43 Hz, 1H), 6.89 (d, J=7.63 Hz, 1H), 7.24 (t, J=7.78Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.24 Hz, 1H).

Example 1562-(3,5-difluorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-(3,5-difluorophenyl)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 410 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.53-1.67 (m, 4H), 2.31-2.42 (m,4H), 3.67 (s, 2H), 3.88 (s, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.04 (d,J=6.41 Hz, 1H), 7.07-7.13 (m, 1H), 7.25 (t, J=7.93 Hz, 1H), 7.36 (s,1H), 7.46 (d, J=8.24 Hz, 1H).

Example 157N²-acetyl-N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-L-leucinamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting (S)-2-acetamido-4-methylpentanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 411 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 0.88 (d, J=6.71 Hz, 3H), 0.90 (d,J=6.71 Hz, 3H), 1.43-1.53 (m, 2H), 1.56-1.66 (m, 5H), 1.87 (s, 3H),2.29-2.43 (m, 4H), 3.88 (s, 2H), 4.39 (dd, J=9.61, 5.34 Hz, 1H), 6.91(d, J=7.63 Hz, 1H), 7.25 (t, J=7.78 Hz, 1H), 7.38 (s, 1H), 7.49 (d,J=8.24 Hz, 1H).

Example 158N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N²,N²-dipropyl-L-alaninamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting (S)-2-(dipropylamino)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 411 (M+H)⁺.

Example 1594-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 4-oxo-4-phenylbutanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 411 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.66 (m, 4H), 2.31-2.42 (m,4H), 2.70 (t, J=6.26 Hz, 2H), 3.32 (t, J=6.26 Hz, 2H), 3.87 (s, 2H),6.88 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.37 (s, 1H), 7.45 (d,J=8.24 Hz, 1H), 7.55 (t, J=7.63 Hz, 2H), 7.66 (t, J=7.32 Hz, 1H), 7.99(t, J=6.41 Hz, 2H).

Example 160N-(2-oxo-2-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylamino)ethyl)benzamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-benzamidoacetic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 417 (M+H)⁺. ¹H NMR (500 MHz,D₂O/dimethylsulfoxide-d₆): δ 1.55-1.66 (m, 4H), 2.31-2.40 (m, 4H), 3.89(s, 2H), 4.04 (s, 2H), 6.92 (d, J=7.93 Hz, 1H), 7.26 (t, J=7.93 Hz, 1H),7.38 (s, 1H), 7.47 (d, J=8.24 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (t,J=7.32 Hz, 1H), 7.85-7.90 (m, 2H).

Example 1613-(3-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(3-methoxyphenyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 418 (M+H)⁺.

Example 1623-(4-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(4-methoxyphenyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 418 (M+H)⁺.

Example 1632-(3,4-dimethylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-(3,4-dimethylphenoxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 418 (M+H)⁺.

Example 164(2R)-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenylbutanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting (R)-2-hydroxy-4-phenylbutanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.65 (m, 4H), 1.80-1.90 (m,1H), 1.95-2.03 (m, 1H), 2.31-2.44 (m, 4H), 2.69 (t, J=7.93 Hz, 2H), 3.88(s, 2H), 3.96 (s, 1H), 4.01 (dd, J=8.09, 4.12 Hz, 1H), 6.91 (d, J=7.63Hz, 1H), 7.17-7.23 (m, 3H), 7.25 (t, J=7.78 Hz, 1H), 7.29 (t, J=7.48 Hz,2H), 7.49 (s, 1H), 7.53 (d, J=7.93 Hz, 1H).

Example 165N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-phenoxybutanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 4-phenoxybutanoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (500 MHz,D₂O/dimethylsulfoxide-d₆): δ 1.55-1.67 (m, 4H), 1.96-2.06 (m, 2H),2.31-2.42 (m, 4H), 2.47 (t, J=7.48 Hz, 2H), 3.88 (s, 2H), 3.99 (t,J=6.26 Hz, 2H), 6.87-6.91 (m, 2H), 6.91-6.96 (m, 2H), 7.24 (t, J=7.78Hz, 1H), 7.26-7.30 (m, 2H), 7.36 (s, 1H), 7.48 (d, J=8.24 Hz, 1H).

Example 1664-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-thien-2-ylbutanamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-oxo-4-(thiophen-2-yl)butanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 422 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.65 (m, 4H), 2.32-2.42 (m,4H), 2.69 (t, J=6.41 Hz, 2H), 3.26 (t, J=6.41 Hz, 2H), 3.87 (s, 2H),6.88 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.25-7.29 (m, 1H),7.37 (s, 1H), 7.44 (d, J=8.24 Hz, 1H), 7.97 (d, J=4.88 Hz, 1H), 7.99 (d,J=2.75 Hz, 1H).

Example 1672-((4-methylpyrimidin-2-yl)thio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-(4-methylpyrimidin-2-ylthio)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 1683-(2-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(2-chlorophenyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 1693-(4-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(4-chlorophenyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 1703-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-phenylpentanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-methyl-2-phenylpentanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 430 (M+H)⁺.

Example 1712-(4-chloro-2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)acetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2-(4-chloro-2-methylphenoxy)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 438 (M+H)⁺.

Example 172N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N′-phenylpentanediamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 5-oxo-5-(phenylamino)pentanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 445 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.65 (m, 4H), 1.84-1.94 (m,2H), 2.31-2.42 (m, 8H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.05 (t,J=7.32 Hz, 1H), 7.24 (t, J=7.93 Hz, 1H), 7.30 (t, J=8.09 Hz, 2H), 7.36(s, 1H), 7.48 (d, J=8.24 Hz, 1H), 7.57 (d, J=7.63 Hz, 2H).

Example 1734-(4-methoxyphenyl)-4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)butanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 4-(4-methoxyphenyl)-4-oxobutanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 446 (M+H)⁺.

Example 174N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-diphenylacetamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 2,2-diphenylacetic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 450 (M+H)⁺.

Example 175N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-(phenylsulfonyl)propanamide

The title compound was prepared according to procedure for EXAMPLE 136,substituting 3-(phenylsulfonyl)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 452 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.52-1.70 (m, 4H), 2.29-2.42 (m,4H), 2.66 (t, J=7.32 Hz, 2H), 3.59 (t, J=7.32 Hz, 2H), 3.87 (s, 2H),6.90 (d, J=7.32 Hz, 1H), 7.20-7.26 (m, 2H), 7.37 (d, J=8.54 Hz, 1H),7.66 (t, J=7.63 Hz, 2H), 7.74 (t, J=7.48 Hz, 1H), 7.91 (d, J=7.32 Hz,2H).

Example 176N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(3-phenoxyphenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(3-phenoxyphenyl)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 466 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.65 (m, 4H), 2.29-2.42 (m,4H), 3.60 (s, 2H), 3.87 (s, 2H), 6.86-6.92 (m, 2H), 6.98-7.03 (m, 3H),7.10 (d, J=7.93 Hz, 1H), 7.16 (t, J=7.48 Hz, 1H), 7.24 (t, J=7.78 Hz,1H), 7.32-7.37 (m, 2H), 7.38-7.42 (m, 2H), 7.46 (d, J=8.24 Hz, 1H).

Example 1774-ethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-ethylbenzoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 388 (M+H)⁺.

Example 1783-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-fluoro-2-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 392 (M+H)⁺.

Example 1795-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 5-fluoro-2-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 392 (M+H)⁺.

Example 1803-fluoro-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-fluoro-4-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 392 (M+H)⁺.

Example 1812,3-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2,3-difluorobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 396 (M+H)⁺.

Example 1822,4-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2,4-difluorobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 396 (M+H)⁺.

Example 1832,5-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2,5-difluorobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 396 (M+H)⁺.

Example 1843,5-difluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3,5-difluorobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m z 396 (M+H)⁺.

Example 185N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-propylbenzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-propylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 402 (M+H)⁺.

Example 1864-isopropyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-isopropylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 402 (M+H)⁺.

Example 1872-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-ethoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 1884-isopropoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-isopropoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.30 (d, J=6.10 Hz, 6H),1.53-1.67 (m, 4H), 2.33-2.46 (m, 4H), 3.91 (s, 2H), 4.67-4.80 (m, 1H),6.94 (d, J=7.63 Hz, 1H), 7.02 (d, J=8.85 Hz, 2H), 7.29 (t, J=7.78 Hz,1H), 7.55 (s, 1H), 7.62 (d, J=8.24 Hz, 1H), 7.89 (d, J=8.85 Hz, 2H).

Example 1894-(diethylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-(diethylamino)benzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 431 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.1 (t, J=7.02 Hz, 6H), 1.57-1.66(m, 4H), 2.34-2.44 (m, 4H), 3.45 (q, J=7.02 Hz, 4H), 3.91 (s, 2H), 6.87(d, J=8.85 Hz, 2H), 6.91 (d, J=7.63 Hz, 1H), 7.27 (t, J=7.93 Hz, 1H),7.55 (s, 1H), 7.62 (d, J=8.24 Hz, 1H), 7.85 (d, J=8.85 Hz, 2H).

Example 1904-butoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-butoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 432 (M+H)⁺.

Example 1912-fluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-fluoro-5-(trifluoromethyl)benzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 446 (M+H)⁺.

Example 1922-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-chloro-5-(trifluoromethyl)benzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 461 (M+H)⁺.

Example 193N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-furamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting furan-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 350 (M+H)⁺.

Example 194N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-furamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting furan-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 350 (M+H)⁺.

Example 1952,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-furamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2,5-dimethylfuran-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 378 (M+H)⁺.

Example 196N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting thiophene-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 366 (M+H)⁺.

Example 197N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting thiophene-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 366 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.66 (m, 4H), 2.32-2.44 (m,4H), 3.92 (s, 2H), 6.96 (d, J=7.63 Hz, 1H), 7.30 (t, J=7.93 Hz, 1H),7.53 (s, 1H), 7.59-7.65 (m, 3H), 8.31 (dd, J=2.75, 1.53 Hz, 1H).

Example 1983-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-methylthiophene-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 380 (M+H)⁺.

Example 1995-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)thiophene-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 5-methylthiophene-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 380 (M+H)⁺.

Example 200N²-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting pyrrole-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 349 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.56-1.66 (m, 4H), 2.33-2.44 (m,4H), 3.91 (s, 2H), 6.18 (dd, J=3.51, 2.29 Hz, 1H), 6.92 (d, J=7.63 Hz,1H), 6.98 (d, J=1.53 Hz, 1H), 7.03-7.07 (m, 1H), 7.27 (t, J=7.93 Hz,1H), 7.53 (s, 1H), 7.60 (d, J=7.93 Hz, 1H).

Example 2011-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-methyl-1H-pyrrole-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 363 (M+H)⁺.

Example 2022,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2,5-dimethyl-1H-pyrrole-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 377 (M+H)⁺.

Example 2031,2,5-trimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-pyrrole-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-methyl-1H-pyrrole-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 363 (M+H)⁺.

Example 204N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting thiazole-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺.

Example 205N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting thiazole-4-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺.

Example 206N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1,3-thiazole-5-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting thiazole-5-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.67 (m, 2H), 2.32-2.44 (m,2H), 3.92 (s, 2H), 7.00 (d, J=7.63 Hz, 1H), 7.32 (t, J=7.93 Hz, 1H),7.49 (s, 1H), 7.59 (d, J=8.24 Hz, 1H), 8.66 (s, 1H), 9.27 (s, 1H).

Example 208N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isoxazole-5-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting isoxazole-5-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 351 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.68 (m, 4H), 2.33-2.45 (m,4H), 3.93 (s, 2H), 7.03 (d, J=7.63 Hz, 1H), 7.22 (d, J=2.14 Hz, 1H),7.34 (t, J=7.93 Hz, 1H), 7.54 (s, 1H), 7.63 (d, J=7.93 Hz, 1H), 8.77 (d,J=1.83 Hz, 1H).

Example 2093,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isoxazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3,5-dimethylisoxazole-4-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 379 (M+H)⁺.

Example 210N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting nicotinic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 361 (M+H)⁺.

Example 211N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)isonicotinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting isonicotinic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 361 (M+H)¹H NMR (500 MHz,D₂O/dimethylsulfoxide-d₆): δ 1.57-1.68 (m, 4H), 2.33-2.45 (m, 4H), 3.94(s, 2H), 7.04 (d, J=7.63 Hz, 1H), 7.36 (t, J=7.78 Hz, 1H), 7.56 (s, 1H),7.66 (d, J=8.24 Hz, 1H), 8.10 (d, J=6.41 Hz, 2H), 8.90 (d, J=6.10 Hz,2H).

Example 2123-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyridine-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-hydroxypicolinic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 377 (M+H)⁺.

Example 2132-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-hydroxynicotinic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 377 (M+H)⁺.

Example 2146-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)nicotinamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 6-hydroxynicotinic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 377 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.53-1.65 (m, 4H), 2.32-2.43 (m,4H), 3.91 (s, 2H), 6.45 (d, J=10.07 Hz, 1H), 6.95 (d, J=7.63 Hz, 1H),7.29 (t, J=7.93 Hz, 1H), 7.46 (s, 1H), 7.57 (d, —=8.24 Hz, 1H), 7.98(dd, J=9.76, 2.75 Hz, 1H), 8.16 (d, J=2.14 Hz, 1H).

Example 215N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-pyridin-2-ylacetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(pyridin-2-yl)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 375 (M+H)⁺.

Example 216N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-pyridin-3-ylacetamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(pyridin-3-yl)acetic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 375 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.66 (m, 4H), 2.30-2.42 (m,4H), 3.88 (s, 2H), 3.98 (s, 2H), 6.94 (d, J=7.32 Hz, 1H), 7.27 (t,J=7.93 Hz, 1H), 7.38 (s, 1H), 7.46 (d, J=8.85 Hz, 1H), 8.04 (dd, J=7.93,5.80 Hz, 1H), 8.52 (d, J=8.24 Hz, 1H), 8.81 (d, J=5.49 Hz, 1H), 8.85 (s,1H).

Example 2175-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 5-methylpyrazine-2-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 376 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.69 (m, 4H), 2.34-2.46 (m,4H), 2.63 (s, 3H), 3.93 (s, 2H), 7.00 (d, J=7.63 Hz, 1H), 7.33 (t,J=8.09 Hz, 1H), 7.68-7.74 (m, 2H), 8.68 (s, 1H), 9.13 (d, J=1.22 Hz,1H).

Example 218N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1H-indole-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1H-indole-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 399 (M+H)⁺.

Example 2195-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-yl)methyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 440 (M+H)⁺.

Example 2206-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2H-chromene-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 6-chloro-2H-chromene-3-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 221

N³,N³-dimethyl-N¹-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-beta-alaninamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-(dimethylamino)propanoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 355 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.66 (m, 4H), 2.30-2.43 (m,4H), 2.77-2.93 (m, 100H), 3.93 (s, 2H), 6.74 (s, 1H), 6.90 (dd, J=8.09,1.37 Hz, 1H), 7.06 (d, J=—7.63 Hz, 1H), 7.37 (t, J=7.78 Hz, 1H).

Example 2224-(2-(3-bromophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 222A 2-(3-bromophenyl)-N-methoxy-N-methylacetamide

To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) inN,N-dimethylformamide (125 ml) was successively addedN,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.9 g,46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). Thereaction mixture was stirred at room temperature overnight, andpartitioned between ethyl acetate and brine. The organic phase waswashed with brine, and concentrated. The residue was purified by flashchromatography on silica gel (50% ethyl acetate in hexane) to providethe title compound. MS (DCI/NH₃) m/z 258 (M+H)⁺.

Example 222B 2-(3-bromophenyl)acetaldehyde

A solution of EXAMPLE 222A (2.5 g, 9.7 mmol) in anhydroustetrahydrofuran (50 ml) was treated with LiAlH₄ (0.37 g, 9.7 mmol) at 0°C. for 10 minutes, and quenched with water. The mixture was partitionedbetween ethyl acetate and saturated ammonium chloride. The organic phasewas washed with water and concentrated. The residue was purified byflash chromatography on silica gel (20% ethyl acetate in hexane) toprovide the title compound. MS (DCI/NH₃) m/z 199 (M+H)⁺.

Example 222C3-(2-(3-bromophenyl)ethylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting EXAMPLE 222B for 2-fluoro-5-formylbenzonitrile. MS(DCI/NH₃) m/z 319 (M+H)⁺.

Example 222D4-(2-(3-bromophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 222C for EXAMPLE 2B. MS (DCI/NH₃) m/z 333(M+H)⁺.

Example 2234-(2-(3-bromo-4-fluorophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 223A 2-(3-bromo-4-fluorophenyl)acetaldehyde

The title compound was prepared according to the procedure for EXAMPLE222, substituting 2-(3-bromo-4-fluorophenyl)acetic acid for2-(3-bromophenyl)acetic acid in EXAMPLE 223B. MS (DCI/NH₃) m/z 216(M+H)⁺.

Example 223B4-(2-(3-bromo-4-fluorophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting EXAMPLE 223A for 2-fluoro-5-formylbenzonitrile. MS(DCI/NH₃) m/z 351 (M+H)⁺.

Example 2244-(2,2,2-trifluoro-1-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 224A3-(2,2,2-trifluoro-1-phenylethylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 2,2,2-trifluoro-1-phenylethanone for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 295 (M+H)⁺.

Example 224B4-(2,2,2-trifluoro-1-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 224A for EXAMPLE 2B. MS (DCI/NH₃) m/z 309(M+H)⁺.

Example 2252-hydroxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-hydroxy-4-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 390 (M+H)⁺.

Example 2264-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-acetylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-(d₆): δ 1.54-1.69 (m, 4H), 2.34-2.46 (m,4H), 2.64 (s, 3H), 3.93 (s, 2H), 6.99 (d, J=7.63 Hz, 1H), 7.32 (t,J=7.93 Hz, 1H), 7.57 (s, 1H), 7.65 (d, J=7.93 Hz, 1H), 8.01-8.05 (m,2H), 8.05-8.10 (m, 2H).

Example 2273-methoxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-methoxy-4-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 2284-ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-ethoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 2293-fluoro-4-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-fluoro-4-methoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 408 (M+H)⁺.

Example 230N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-1-naphthamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-naphthoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 410 (M+H)⁺.

Example 231N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-naphthamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-naphthoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 410 (M+H)⁺.

Example 2325-chloro-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-hydroxy-5-methylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 390 (M+H)⁺.

Example 2334-tert-butyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-tert-butylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 416 (M+H)⁺.

Example 2344-(acetylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-acetamidobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 417 (M+H)⁺; ¹H NMR(500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.53-1.68 (m, 4H), 2.10 (s, 3H),2.33-2.44 (m, 4H), 3.92 (s, 2H), 6.95 (d, J=7.93 Hz, 1H), 7.30 (t,J=7.93 Hz, 1H), 7.56 (s, 1H), 7.63 (d, J=7.63 Hz, 1H), 7.70 (d, J=8.85Hz, 2H), 7.90 (d, J=8.85 Hz, 2H).

Example 235N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-propoxybenzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-propoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₄) m/z 418 (M+H)⁺.

Example 2361-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-naphthamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 1-hydroxy-2-naphthoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 426 (M+H)⁺.

Example 2372-chloro-5-(methylthio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-chloro-5-(methylthio)benzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 440 (M+H)⁺.

Example 2383,4-diethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3,4-diethoxybenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 2392-benzyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-benzoylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 450 (M+H)⁺.

Example 2402-anilino-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared as a trifluoroacetic acid salt accordingto the procedure for EXAMPLE 136, substituting 2-(phenylamino)benzoicacid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 451(M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.55-1.68 (m, 4H),2.31-2.45 (m, 4H), 3.91 (s, 2H), 6.91-6.99 (m, 3H), 7.13 (d, J=7.63 Hz,2H), 7.27-7.34 (m, 4H), 7.38-7.42 (m, 1H), 7.49 (s, 1H), 7.58 (d, J=8.85Hz, 1H), 7.71-7.75 (m, 1H).

Example 2412-benzoyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared as according to the procedure forEXAMPLE 136, substituting 2-benzoylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 464 (M+H)⁺.

Example 242N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(2-phenylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-phenethylbenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 464 (M+H)⁺.

Example 2435-bromo-2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 5-bromo-2-chlorobenzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m z 472 (M+H)⁺.

Example 2442-(4-methylbenzoyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-(4-methylbenzoyl)benzoic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 478 (M+H)⁺.

Example 2452-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 2-iodobenzoic acid for 1-methylcyclopropaneccarboxylicacid. MS (DCI/NH₃) m/z 486 (M+H)⁺.

Example 2463-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 3-iodobenzoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 486 (M+H)⁺.

Example 2474-iodo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting 4-iodobenzoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 486 (M+H)⁺.

Example 248N-(2′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1-biphenyl-3-yl)acetamide

The title compound was prepared as a free base according to theprocedure for EXAMPLE 39, substituting 3-acetamidophenylboronic acid for3-pyridineboronic acid, but eliminating the last HCl salt formationstep. MS (DCI/NH₃) m/z 392 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.58-1.67 (m, 4H), 2.05 (s, 3H), 2.33-2.39 (m,2H), 2.40-2.46 (m, 2H), 3.95 (s, 2H), 7.16 (d, J=7.02 Hz, 1H), 7.18-7.21(m, 1H), 7.22-7.27 (m, 1H), 7.30 (dd, J=7.63, 2.14 Hz, 1H), 7.38 (t,J=7.93 Hz, 1H), 7.59 (d, J=7.32 Hz, 1H), 7.76 (s, 1H), 10.04 (br s, 1H),12.61 (br s, 1H).

Example 2494-((6-fluoro-3′-(methylsulfonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as free base according to the procedurefor EXAMPLE 39, substituting 3-(methylsulfonyl)phenylboronic acid for3-pyridineboronic acid, but eliminating the last HCl salt formationstep. MS (DCI/NH₃) m/z 413 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.57-1.73 (m, 4H), 2.34-2.41 (m, 2H), 2.41-2.48(m, 2H), 3.28 (s, 3H), 3.98 (s, 2H), 7.24-7.28 (m, 1H), 7.28-7.33 (m,1H), 7.47 (dd, J=7.63, 2.14 Hz, 1H), 7.77 (t, J=7.78 Hz, 1H), 7.90 (d,J=7.93 Hz, 1H), 7.96-8.00 (m, 1H), 8.04 (s, 1H), 12.61 (br s, 1H).

Example 2504-((6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as free base according to the procedurefor EXAMPLE 39, substituting 3-(pyrrolidine-1-carbonyl)phenylboronicacid for 3-pyridineboronic acid, but eliminating the last HCl saltformation step. MS (DCI/NH₃) m/z 432 (M+H)⁺.

Example 2514-((6-fluoro-4′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as free base according to the procedurefor EXAMPLE 39, substituting 4-(pyrrolidine-1-carbonyl)phenylboronicacid for 3-pyridineboronic acid, but eliminating the last HCl saltformation step. MS (DCI/NH₃) m/z 432 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.57-1.68 (m, 4H), 1.78-1.93 (m, 4H), 2.32-2.39(m, 2H), 2.40-2.47 (m, 2H), 3.39-3.53 (m, 4H), 3.95 (s, 2H), 7.21-7.24(m, 1H), 7.24-7.31 (m, 1H), 7.39 (dd, J=7.63, 1.86 Hz, 1H), 7.55-7.59(m, 2H), 7.60-7.64 (m, 2H), 12.60 (br s, 1H).

Example 2522′-fluoro-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared as free base according to the procedurefor EXAMPLE 39, substituting 3-carbamoylphenylboronic acid for3-pyridineboronic acid, but eliminating the last HCl salt formationstep. MS (DCI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.55-1.72 (m, 4H), 2.33-2.41 (m, 2H), 2.41-2.47(m, 2H), 3.97 (s, 2H), 7.19-7.24 (m, 1H), 7.24-7.30 (m, 1H), 7.42 (dd,J=7.63, 2.14 Hz, 1H), 7.44 (s, 1H), 7.56 (t, J=7.78 Hz, 1H), 7.68 (d,J=7.63 Hz, 1H), 7.88-7.92 (m, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 12.61 (s,1H).

Example 2532′-fluoro-N,N-dimethyl-5′-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-1,1′-biphenyl-4-carboxamide

The title compound was prepared as free base according to the procedurefor EXAMPLE 39, substituting 4-(dimethylcarbamoyl)phenylboronic acid for3-pyridineboronic acid, but eliminating the last HCl salt formationstep. MS (DCI/NH₃) m/z 406 (M+H)⁺. ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.56-1.69 (m, 4H), 2.31-2.40 (m, 2H), 2.40-2.47(m, 2H), 2.95 (s, 3H), 3.00 (s, 3H), 3.96 (s, 2H), 7.20-7.24 (m, 1H),7.24-7.30 (m, 1H), 7.40 (dd, J=7.48, 1.98 Hz, 1H), 7.49-7.52 (m, 1H),7.56-7.59 (m, 2H), 7.60-7.65 (m, 1H), 12.61 (br s, 1H).

Example 2544-(3,3,3-trifluoro-2-phenylpropyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 254A3-(1,1,1-trifluoro-3-phenylpropan-2-ylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 1,1,1-trifluoro-3-phenylpropan-2-one for2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃) m/z 309 (M+H)⁺.

Example 254B4-(3,3,3-trifluoro-2-phenylpropyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 254A for EXAMPLE 2B. MS (DCI/NH₃) m/z 323(M+H)⁺.

Example 255 4-(2-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared as a side product according to theprocedure for EXAMPLE 101, substituting EXAMPLE 222 for EXAMPLE 103. MS(DCI/NH₃) m/z 255 (M+H)⁺.

Example 2564-(2-(3-bromophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 256A 2-(3-bromophenyl)-N-methoxy-N-methylpropanamide

A solution of EXAMPLE 222A (3.5 g, 13.56 mmol) in anhydroustetrahydrofuran (50 ml) was treated with 1N sodium dicyanamide vsolution in tetrahydrofuran (16 ml, 16.27 mmol) at −78° C. for 1 hour.Iodomethane (3.85 g, 27.1 mmol) was added through a syringe, and themixture was allowed to warm up to room temperature for 2 hours. Themixture was concentrated, and the residue was partitioned between ethylacetate and brine. The organic phase was concentrated, the residue waspurified by flash column chromatography (30% ethyl acetate in hexane) toprovide the title compound. MS (DCI/NH₃) m/z 273 (M+H)⁺.

Example 256B 2-(3-bromophenyl)propanal

The title compound was prepared according to the procedure for EXAMPLE222B, substituting EXAMPLE 256A for EXAMPLE 222A. MS (DCI/NH₃) m/z 214(M+H)⁺.

Example 256C3-(2-(3-bromophenyl)propylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 256B for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃)m/z 334 (M+H)⁺.

Example 256D4-(2-(3-bromophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 256C for EXAMPLE 2B. MS (DCI/NH₃) m/z 348(M+H)⁺.

Example 257 tert-butyl2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1-carboxylateExample 257A 4-benzyl 1-tert-butyl2-(methoxy(methyl)carbamoyl)piperazine-1,4-dicarboxylate

The title compound was prepared according to the procedure for EXAMPLE222A, substituting4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid for 2-(3-bromophenyl)acetic acid. MS (DCI/NH₃) m/z 408 (M+H)⁺.

Example 257B 4-benzyl 1-tert-butyl 2-formylpiperazine-1,4-dicarboxylate

The title compound was prepared according to the procedure for EXAMPLE222B, substituting EXAMPLE 257A for EXAMPLE 222A. MS (DCI/NH₃) m/z 349(M+H)⁺.

Example 257C 4-benzyl 1-tert-butyl2-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)piperazine-1,4-dicarboxylate

The title compound was prepared according to the procedure for EXAMPLE1C, substituting EXAMPLE 257B for 2-fluoro-5-formylbenzonitrile. MS(DCI/NH₃) m/z 469 (M+H)⁺.

Example 257D 4-benzyl 1-tert-butyl2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1,4-dicarboxylate

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 257C for EXAMPLE 2B. MS (DCI/NH₃) m/z 483(M+H)⁺.

Example 257E tert-butyl2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1-carboxylate

A solution of EXAMPLE 257D (0.77 g, 1.6 mmol) in tetrahydrofuran (100ml) was treated with 10% palladium on carbon (85 mg, 0.8 mmol) at roomtemperature under hydrogen (balloon) overnight. The catalyst was removedby filtration, and the filtrate was concentrated. The residue waspurified by flash chromatography (0-15% gradient of methanol in CH₂Cl₂)to provide the title compound. MS (DCI/NH₃) m/z 349 (M+H)⁺.

Example 258 4-benzyl 1-tert-butyl2-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)piperazine-1,4-dicarboxylate

The title compound was prepared as described in EXAMPLE 257D. MS(DCI/NH₃) m/z 483 (M+H)⁺.

Example 2594-(2-(3-nitrophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 259A N-methoxy-N-methyl-2-(3-nitrophenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE222A, substituting 3-nitrobenzoic acid for 2-(3-bromophenyl)acetic acid.MS (DCI/NH₃) m/z 225 (M+H)⁺.

Example 259B 2-(3-nitrophenyl)acetaldehyde

The title compound was prepared according to the procedure for EXAMPLE222B, substituting EXAMPLE 259A for EXAMPLE 222A.

Example 259C3-(2-(3-nitrophenyl)ethylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting EXAMPLE 259B for 2-fluoro-5-formylbenzonitrile. MS(DCI/NH₃) m/z 286 (M+H)⁺.

Example 259D 4-(2-(3-nitrophenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 259C for EXAMPLE 2B. MS (DCI/NH₃) m/z 300(M+H)⁺.

Example 2604-(2-(3-aminophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A suspension of EXAMPLE 259 (110 mg, 0.17 mmol) in methanol (20 ml) wastreated with Raney Nickel (20 mg) at room temperature under hydrogen(balloon) overnight. The solid material was filtered off, and thefiltrate was concentrated to give the title compound. MS (DCI/NH₃) m/z270 (M+H)⁺.

Example 2614-(piperazin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 258 (35 mg, 0.1 mmol) in trifluoroacetic acid (5ml) was stirred at room temperature for 1 hour, and was concentrated.The residue was purified by HPLC (Zorbax® C-18 ODS packing material[Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroaceticacid/CH₃CN/H₂O) to provide the title compound as a trifluoroacetic acidsalt. MS (DCI/NH₃) m/z 249 (M+H)⁺.

Example 2624-(2-(3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 260 (100 mg, 0.37 mmol) in methylene chloride(5 mL) was added 4-chlorobutyrlchloride (52.3 mg, 0.37 mmol) andtriethylamine (0.12 mL, 0.45 mmol). The mixture was stirred at roomtemperature overnight, and was concentrated. The residue was dissolvedin absolute ethanol (5 mL), and was treated with sodium ethoxide (0.2mL, 21 wt % in ethanol) at room temperature for 16 hours. 1 mL of 2N HClwas added, and the mixture was concentrated. The residue was separatedby HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, SantaClara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O) to provide thetitle compound as a trifluoroacetic acid salt. MS (DCI/NH₃) m/z 338(M+H)⁺.

Example 263N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-2-phenoxyacetamide

A solution of 2-phenoxyacetic acid (28 mg, 0.186 mmol) in anhydrousdichloromethane (3 ml) was treated with oxalyl chloride (35.3 mg, 0.186mmol) and a drop of N,N-dimethylformamide at room temperature for 1hour, and was concentrated. The residue was re-dissolved in anhydrousdichloromethane (5 ml). A suspension of EXAMPLE 260 (50 mg, 0.186 mmol)in anhydrous tetrahydrofuran (2 ml) was then added. The reaction mixturewas stirred at room temperature overnight, and was concentrated. Theresidue was purified by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid,CH₃CN/H₂O) to provide the title compound as a trifluoroacetic acid salt.MS (DCI/NH₃) m/z 404 (M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ1.60-1.70 (m, 4H), 2.35-2.39 (m, 2H), 2.42-2.50 (m, 2H), 2.66-2.93 (m,4H), 4.68 (s, 2H), 6.82-7.09 (m, 4H), 7.23 (t, J=7.80 Hz, 1H), 7.24-7.38(m, 2H), 7.40-7.60 (m, 2H), 10.01 (s, 1H) 12.54 (s, 1H).

Example 2644-(2-(6-fluoro-3′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A microwave vial charged with EXAMPLE 223 (50 mg, 0.14 mmol),dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.014 mmol),3-(morpholine-4-carbonyl)phenylboronic acid (40 mg, 0.17 mmol), amixture of DME(7)/water(3)/ethanol(2) (3 ml), and sodium carbonatesolution (2M, 0.1 ml) was heated in a CEM Explorer® microwave reactor(Matthews, N.C.) at 150° C. for 15 minutes. After cooling, the reactionmixture was diluted with methanol (20 ml), and filtered. The filtratewas concentrated, and the residue was separated by HPLC (Zorbax® C-18ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound. MS(DCI/NH₃) m/z 462 (M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ1.60-1.67 (m, 4H), 2.35-2.39 (m, 2H), 2.44-2.50 (m, 2H), 2.75-3.01 (m,4H), 3.44-3.73 (m, 8H), 7.17-7.28 (m, 1H), 7.27-7.34 (m, 1H), 7.38-7.47(m, 1H), 7.50-7.67 (m, 4H), 12.55 (s, 1H).

Example 265 methyl3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoate

The title compound was prepared according to the procedure for EXAMPLE66, substituting EXAMPLE 222 for EXAMPLE 66B. MS (DCI/NH₃) m/z 313(M+H)⁺.

Example 266 methyl3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoate

The title compound was prepared according to the procedure for EXAMPLE66, substituting EXAMPLE 256 for EXAMPLE 66B. MS (DCI/NH₃) m/z 237(M+H)⁺.

Example 2674-(2-(6-fluoro-4′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE264, substituting 4-(morpholine-4-carbonyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 462(M+H)⁺.

Example 2684-(2-(6-fluoro-2′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE264 substituting 2-(pyrrolidine-1-carbonyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 446(M+H)⁺.

Example 2694-(2-(6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-(pyrrolidine-1-carbonyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 446(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.64-1.81 (m, 4H), 1.83-2.03 (m, 4H),2.43-2.47 (m, 2H), 2.56-2.59 (m, 2H), 2.76-2.88 (m, 2H), 2.93-3.06 (m,2H), 3.48 (t, J=6.54 Hz, 2H), 3.67 (t, J=6.74 Hz, 2H), 7.01-7.11 (m,1H), 7.11-7.21 (m, 1H), 7.29 (dd, J=7.54, 2.38 Hz, 1H), 7.39-7.54 (m,2H), 7.55-7.62 (m, 1H), 7.69 (s, 1H), 10.10 (s, 1H).

Example 270N-cyclopropyl-2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-(cyclopropylcarbamoyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 432(M+H)⁺.

Example 271N-(2-(dimethylamino)ethyl)-2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acidfor 3-(morpholine-4-carbonyl)-phenylboronic acid. MS (DCI/NH₃) m/z 463(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 2.28-2.39 (m, 2H), 2.35 (m, 3H), 2.45(s, 6H), 2.60-2.69 (m, 2H), 2.73-2.82 (m, 2H), 2.87 (t, J=7.14 Hz, 2H),3.01 (t, J=7.14 Hz, 2H), 3.54-3.64 (m, 1H), 3.69 (q, J=5.29 Hz, 2H),6.95-7.10 (m, 1H), 7.10-7.20 (m, 1H), 7.35-7.53 (m, 2H), 7.65-7.80 (m,2H), 7.79-7.88 (m, 1H).

Example 2722′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-carbamoylphenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 392(M+H)⁺; ¹H NMR (500 MHz, pyridine-d₅): δ 1.54 (s, 4H), 2.27 (s, 2H),2.70 (s, 2H), 2.76-2.95 (m, 2H), 2.98-3.21 (m, 2H), 7.19-7.27 (m, 2H),7.31 (s, 1H), 7.49 (d, J=7.02 Hz, 1H), 7.82 (d, J=7.32 Hz, 1H), 8.42 (d,J=7.63 Hz, 1H), 8.47 (s, 1H), 8.68 (s, 1H), 9.02 (s, 1H), 14.05 (s, 1H).

Example 273N-(2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)methanesulfonamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-(methylsulfonamido)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 442(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 2.31-2.48 (m, 4H), 2.59 (m, 4H),2.77-2.96 (m, 4H), 3.02 (t, J=7.80 Hz, 3H), 6.92-7.03 (m, 1H), 7.02-7.12(m, 1H), 7.10-7.22 (m, 2H), 7.27-7.33 (m, 1H), 7.32-7.47 (m, 2H), 10.96(s, 1H).

Example 274N-(2′-fluoro-5′-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting 3-acetamidophenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 406(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 2.06-2.21 (m, 4H), 2.25 (s, 3H), 2.34(m, 2H), 2.58 (m, 2H), 2.80-2.94 (m, 2H), 2.92-3.06 (m, 2H), 6.93-7.10(m, 2H), 7.10-7.19 (m, 1H), 7.23 (d, J=4.36 Hz, 1H), 7.27-7.33 (m, 1H),7.38 (t, J=7.73 Hz, 1H), 7.67-7.76 (m, 1H), 11.25 (s, 1H).

Example 2754-(2-(6-fluoro-3′-(morpholin-4-ylcarbonyl)-1,1′-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE264 substituting EXAMPLE 293 for EXAMPLE 223. MS (DCI/NH₃) m/z 476(M+H)⁺.

Example 2764-(2-(6-fluoro-3′-(pyrrolidin-1-ylcarbonyl)-1,1′-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE264 substituting EXAMPLE 293 for EXAMPLE 223, and3-(pyrrolidine-1-carbonyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 460(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (d, J=6.74 Hz, 3H), 1.61-1.78(m, 4H), 1.76-2.06 (m, 4H), 2.26-2.45 (m, 2H), 2.49-2.67 (m, 2H), 2.84(m, 2H), 3.21-3.36 (m, 1H), 3.40-3.57 (m, 2H), 3.59-3.83 (m, 2H),7.13-7.23 (m, 1H), 7.36 (t, J=7.93 Hz, 1H), 7.40-7.51 (m, 3H), 7.55-7.64(m, 1H), 7.73 (s, 1H) 9.98 (s, 1H).

Example 277N-cyclopropyl-2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 293 for EXAMPLE 223, and3-(cyclopropylcarbamoyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 446(M+H)⁺.

Example 2784-(3-amino-4-chlorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2, substituting 4-chloro-3-nitrobenzaldehyde for4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH₃) m/z 290 (M+H)⁺.

Example 2794-(3-amino-4-methoxybenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2, substituting 4-methoxy-3-nitrobenzaldehyde for4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH₃) m/z 286 (M+H)⁺.

Example 2804-(3-amino-4-hydroxybenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2, substituting 4-hydroxy-3-nitrobenzaldehyde for4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH₃) m/z 272 (M+H)⁺.

Example 2814-(3-amino-4-methylbenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2, substituting 4-methyl-3-nitrobenzaldehyde for4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH₃) m/z 270 (M+H)⁺.

Example 282N-(2-(dimethylamino)ethyl)-3′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 256 for EXAMPLE 223, and3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 459(M+H)⁺.

Example 2833′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 256 for EXAMPLE 223, and3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 388 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ 1.40 (d,J=7.14 Hz, 3H), 1.53-1.81 (m, 4H), 2.25-2.59 (m, 4H), 2.91 (d, J=7.14Hz, 2H), 3.31-3.41 (m, 1H), 7.23 (d, J=7.54 Hz, 1H), 7.36 (t, J=7.93 Hz,1H), 7.42-7.51 (m, 2H), 7.50-7.59 (m, 1H), 7.73 (d, J=7.93 Hz, 1H),7.79-7.91 (m, 1H), 8.09 (s, 1H).

Example 284N-(3′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 256 for EXAMPLE 223, and3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ 1.40 (d,J=7.12 Hz, 3H), 1.50-1.78 (m, 4H), 2.16 (s, 3H), 2.36-2.53 (m, 4H), 2.83(m, 1H), 2.88 (d, J=7.46 Hz, 2H), 7.16-7.23 (m, 1H), 7.22-7.29 (m, 1H),7.29-7.36 (m, 2H), 7.36-7.45 (m, 2H), 7.47-7.67 (m, 1H), 7.72 (t, J=1.86Hz, 1H).

Example 2853′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamideExample 285A 1-bromo-3-(1-bromoethyl)benzene

A solution of 3-bromoethyl benzene (2 g, 11 mmol). N-bromosuccinimide(91.9 g, 11 mmol) and azobisisobutyronitrile (10 mg, 0.06 mmol) inchloroform (30 ml) was stirred at 65° C. under nitrogen for 18 hours.After cooling, the reaction mixture was concentrated, and the residuewas partitioned between ethyl acetate and brine. The organic layer waswashed with brine, and was concentrated. The residue was separated byflash chromatography on silica gel (10% ethyl acetate in hexane) toprovide the title compound. MS (DCI/NH₃) m/z 262 (M+H)⁺.

Example 285B (1-(3-bromophenyl)ethyl)triphenylphosphonium bromide

A solution of EXAMPLE 285A (1.0 g, 3.8 mmol) and triphenylphosphine (1.1g, 4.2 mmol) in toluene (15 ml) was heated at 120° C. under nitrogen forthree days. After cooling to room temperature, the solid material wascollected by filtration, washed with toluene, and dried to provide thetitle compound.

Example 285C3-(1-(3-bromophenyl)ethylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

A suspension of EXAMPLE 285B (1.88 g, 3.4 mmol) in tetrahydrofuran (100ml) was treated with potassium t-butoxide (1N solution intetrahydrofuran, 3.4 ml, 3.4 mmol) at −78° C. for 1 hour, and wasallowed to warm up to 0° C. over 30 minutes. A solution of4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.54 g, 3.4 mmol) intetrahydrofuran (10 ml) was then added. The reaction mixture was warmedup to room temperature, and stirred at room temperature for additional 4hours. After quenching with water, the reaction mixture was partitionedbetween ethyl acetate and brine. The organic phase was washed withbrine, and concentrated. The residue was separated by flashchromatography (20% ethyl acetate in hexane) to provide the titlecompound. MS (DCI/NH₃) m/z 320 (M+H)⁺.

Example 285D4-(1-(3-bromophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 285C for EXAMPLE 2B. MS (DCI/NH₃) m/z 334(M+H)⁺.

Example 285E3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 285D for EXAMPLE 223, and3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 374 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD): δ 1.59 (d,J=7.12 Hz, 3H), 1.61-1.81 (m, 4H), 2.10-2.22 (m, 1H), 2.39-2.55 (m, 2H),2.61-2.73 (m, 1H), 4.32 (q, J=6.78 Hz, 1H), 7.08-7.21 (m, 1H), 7.35-7.43(m, 1H), 7.48-7.59 (m, 3H), 7.75 (d, J=7.80 Hz, 1H), 7.80-7.87 (m, 1H),8.06-8.11 (m, 1H).

Example 286N-(3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 285D for EXAMPLE 223, and3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 388 (M+H)⁺; ¹H NMR (300 MHz, CD OD): δ 1.58 (d,J=7.12 Hz, 3H), 1.60-1.82 (m, 4H), 2.14 (s, 3H), 2.10-2.23 (m, 1H),2.47-2.55 (m, 2H), 2.60-2.73 (m, 1H), 4.30 (q, J=6.78 Hz, 1H), 7.15 (d,J=7.46 Hz, 1H), 7.23-7.30 (m, 1H), 7.31-7.40 (m, 2H), 7.41-7.47 (m, 1H),7.47-7.56 (m, 1H), 7.56-7.69 (m, 1H), 7.77 (t, J=1.86 Hz, 1H).

Example 287N-(2-(dimethylamino)ethyl)-3′-(1-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 285D for EXAMPLE 223, and3-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 445(M+H)⁺.

Example 2883-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)benzoicacid

A solution of EXAMPLE 266 (50 mg, 0.16 mmol) in tetrahydrofuran (10 ml)was treated with a solution of LiOH.H₂O (100 mg, 4 mmol) in water (4 ml)at 50° C. overnight. The mixture was concentrated, and the residue waspurified by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound. MS (DCI/NH₃) m/z 313 (M+H)⁺.

Example 289N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide

To a solution of 4-(4-methoxyphenyl)-4-oxobutanoic acid (29 mg, 0.14mmol) in dioxane (1.5 mL) was added2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) (42 mg) andN,N′-diisopropylethylamine (32 μL). The mixture was stirred at roomtemperature for 15 minutes, and EXAMPLE 2 (25 mg, 0.091 mmol) was added.The reaction mixture was stirred at room temperature for 16 hours, andwas concentrated. The crude was separated by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as atrifluoroacetic acid salt. MS (DCI/NH₃) m/z 464 (M+H)⁺; ¹H NMR (500 MHz,dimethylsulfoxide-d₆): δ 1.53-1.66 (m, 4H), 2.29-2.40 (m, 4H), 2.74 (t,J=6.41 Hz, 2H), 3.25 (t, J=6.56 Hz, 2H), 3.84 (s, 2H), 3.85 (s, 3H),6.88-6.96 (m, 1H), 7.05 (d, J=8.85 Hz, 2H), 7.12-7.20 (m, 1H), 7.74 (d,J=6.41 Hz, 1H), 7.97 (d, J=9.15 Hz, 2H), 9.75 (br s, 1H), 12.60 (br s,1H).

Example 2901-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione

To a solution of EXAMPLE 2 (100 mg, 0.37 mmol) in acetic acid (8 mL) wasadded 3,4-dimethylfuran-2,5-dione (46 mg, 0.37 mmol). The reactionmixture was heated at 80° C. for 16 hours, and concentrated. The residuewas separated by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CNH₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 382 (M+H)⁺; ¹H NMR (500 MHz, dimethylsulfoxide-d₆): δ1.56-1.68 (m, 4H), 1.98 (s, 6H), 2.30-2.43 (m, 4H), 3.93 (s, 2H), 7.18(dd, J=7.02, 1.53 Hz, 1H), 7.31-7.35 (m, 2H), 12.63 (br s, 1H).

Example 2913-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione

To a suspension of EXAMPLE 2 (210 mg, 0.77 mmol) in acetonitrile (8 mL)was added 3-oxabicyclo(3.1.0)hexane-2,4-dione (95 mg, 0.85 mmol) andstirred at 80° C. for 16 hours. The reaction mixture was cooled andconcentrated on a rotary evaporator. The residual solid was dissolved indioxane (4 mL), and treated with O-(benzotriazol-1-yl,N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 0.99 mmol) andN,N′-diisopropylethylamine (0.3 mL, 1.69 mmol) at room temperature foran additional 16 hours. The reaction mixture was concentrated, andseparated by HPLC (Zorbax® C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH₃CN/H₂O)to provide the title compound as a trifluoroacetic acid salt. MS(DCI/NH₃) m/z 368 (M+H)⁺; ¹H NMR (400 MHz, dimethylsulfoxide-d₆): δ1.57-1.64 (m, 4H), 1.66-1.72 (m, 2H), 2.32-2.41 (m, 4H), 2.75 (dd,J=7.82, 3.22 Hz, 2H), 3.91 (s, 1H), 7.16 (d, J=7.36 Hz, 1H), 7.27-7.29(m, 1H), 7.29-7.32 (m, 1H), 12.61 (br s, 1H).

Example 2924-((4-(phenoxyacetyl)piperazin-2-yl)methyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 258 (138 mg, 0.29 mmol) in methylene chloride (10ml) was treated with trifluoroacetic acid (2 ml) at 40° C. for 2 hours,and concentrated. The residue was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as TFAsalt. MS (DCI/NH₃) m/z 383 (M+H)⁺.

Example 2934-(2-(3-bromo-4-fluorophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 293A 2-(3-bromo-4-fluorophenyl)-N-methoxy-N-methylacetamide

The title compound was prepared according to the procedure for EXAMPLE222A, substituting 2-(3-bromo-4-fluorophenyl)acetic acid for2-(3-bromophenyl)acetic acid. MS (DCI/NH₃) m/z 276 (M+H)⁺.

Example 293B 2-(3-bromo-4-fluorophenyl)-N-methoxy-N-methylpropanamide

The title compound was prepared according to the procedure for EXAMPLE256A, substituting EXAMPLE 293A for EXAMPLE 222A. MS (DCI NH₃) m/z 291(M+H)⁺.

Example 293C 2-(3-bromo-4-fluorophenyl)propanal

The title compound was prepared according to the procedure for EXAMPLE256B, substituting EXAMPLE 293B for EXAMPLE 256A. MS (DCI/NH₃) m/z 232(M+H)⁺.

Example 293D3-(2-(3-bromo-4-fluorophenyl)propylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE1C, substituting 293C for 2-fluoro-5-formylbenzonitrile. MS (DCI/NH₃)m/z 352 (M+H)⁺.

Example 293E4-(2-(3-bromo-4-fluorophenyl)propyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 293D for EXAMPLE 2B. MS (DCI/NH₃) m/z 366(M+H)⁺.

Example 2944-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-4-phenylbutanamide

A mixture of 4-oxo-4-phenylbutanoic acid (50 mg, 0.28 mmol),2-(3H-(1,2,3)triazolo(4,5-b)pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (106 mg, 0.28 mmol) and Hunig's base (120 mg, 0.9 mmol) in anhydrousN,N-dimethylformamide (0.5 ml) was stirred at room temperature for 10minutes, and EXAMPLE 260 (50 mg, 0.18 mmol) was added in one portion.The reaction mixture was stirred at room temperature for another 1 hour,and was diluted with 5 mL of methanol. The solid material was collectedby filtration, washed with methanol, and dried to provide the titlecompound. MS (DCI/NH₃) m/z 430 (M+H)⁺. ¹H NMR (300 MHz,dimethylsulfoxide-d₆): δ 1.54-1.77 (m, 4H), 2.30-2.42 (m, 2H), 2.42-2.49(m, 2H), 2.65-2.79 (m, 4H), 2.79-2.89 (m, 2H), 3.30-3.38 (m, 2H), 6.90(d, J=7.80 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.38-7.49 (m, 2H), 7.54 (t,J=7.46 Hz, 2H), 7.61-7.69 (m, 1H), 7.99 (t, J=6.61 Hz, 2H), 9.96 (s,1H), 12.52 (s, 1H).

Example 2952′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 293 for EXAMPLE 223, and3-carbamoylphenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 406 (M+H)⁺.

Example 296N-(2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-biphenyl-3-yl)acetamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 293 for EXAMPLE 223, and3-acetamidophenylboronic acid for 3-(morpholine-4-carbonyl)phenylboronicacid. MS (DCI/NH₃) m/z 420 (M+H)⁺.

Example 297N-((2′-fluoro-5′-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)-1,1′-yl)ethyl)-biphenyl-3-yl)methyl)methanesulfonamide

The title compound was prepared according to the procedure for EXAMPLE264, substituting EXAMPLE 293 for EXAMPLE 223, and3-(methylsulfonamidomethyl)phenylboronic acid for3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH₃) m/z 470(M+H)⁺.

Example 2982-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione

The title compound was prepared according to the procedure for EXAMPLE291, substituting hexahydroisobenzofuran-1,3-dione foroxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH₃) m/z 410 (M+H)⁺; ¹H NMR(300 MHz, dimethylsulfoxide-d₆): δ 1.31-1.53 (m, 5H), 1.57-1.68 (m, 4H),1.66-1.78 (m, 3H), 1.76-1.92 (m, 2H), 2.29-2.43 (m, 4H), 3.93 (s, 2H),7.12-7.17 (m, 1H), 7.28-7.33 (m, 1H), 7.33-7.37 (m, 1H), 12.63 (br s,1H).

Example 2991-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione

The title compound was prepared according to the procedure for EXAMPLE291, substituting 3,3-dimethyldihydrofuran-2,5-dione foroxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH₃) m/z 384 (M+H)⁺; ¹H NMR(300 MHz, dimethylsulfoxide-d₆): δ 1.31 (s, 6H), 1.54-1.70 (m, 4H),2.30-2.44 (m, 4H), 2.78 (s, 2H), 3.94 (s, 2H), 7.19 (d, J=7.46 Hz, 1H),7.30-7.33 (m, 1H), 7.35 (s, 1H), 12.62 (br s, 1H).

Example 3004-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 300A 4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzaldehyde

A 100 mL round bottom flask was charged with3-bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol),tris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.493 mmol), Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (428 mg, 0.739 mmol),and cesium carbonate (2.4 g, 7.39 mmol). The mixture was purged withnitrogen, and anhydrous dioxane (15 mL), and 5-methylpyrrolidinone(0.586 g, 5.91 mmol) were added. The reaction mixture was purged withnitrogen again, and heated at 100° C. for 20 hours. After cooling toroom temperature, the reaction mixture was partitioned between ethylacetate and brine. The organic phase was dried over MgSO₄, filtered andconcentrated. The residue was separated by flash chromatography (50%ethyl acetate in hexane) to provide the title compound. MS (DCI/NH₃) m/z222 (M+H)⁺.

Example 300B4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 1B (486 mg, 1.16 mmol), EXAMPLE 300A (265 mg) andtriethylamine (0.16 mL) in dichloromethane (8 mL) was stirred at roomtemperature for 16 hours, and concentrated. The residue was dissolved inethanol (5 mL) and treated with hydrazine monohydrate (0.11 mL) at 80°C. for 2 hours. The mixture was allowed to cool and the precipitatedsolid was filtered and dried to provide the title compound. MS (DCI/NH₃)m/z 356 (M+H)⁺; ¹H NMR (400 MHz, dimethylsulfoxide-d₆): δ 1.02 (d,J=6.14 Hz, 3H), 1.57-1.63 (m, 4H), 1.64-1.72 (m, 1H), 2.27-2.34 (m, 1H),2.34-2.40 (m, 4H), 2.41-2.46 (m, 2H), 3.90 (s, 2H), 4.08 (q, J=6.44 Hz,1H), 7.10-7.14 (m, 1H), 7.14-7.18 (m, 1H), 7.20-7.27 (m, 1H), 12.61 (s,1H).

Example 3014-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 301A 4-fluoro-3-(2-oxooxazolidin-3-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting oxazolidin-2-one for 5-methylpyrrolidinone. MS(DCI/NH₃) m/z 210 (M+H)⁺.

Example 301B4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 301A for EXAMPLE 300A. MS (DCI/NH₃) m/z 344(M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ 1.55-1.75 (m, 4H),2.30-2.45 (m, 4H), 3.90 (s, 2H), 3.98 (t, J=7.93 Hz, 2H), 4.45 (dd,J=8.72, 7.14 Hz, 2H), 7.11-7.17 (m, 1H), 7.25 (dd, J=10.91, 8.53 Hz,1H), 7.36 (dd, J=7.54, 2.38 Hz, 1H), 12.61 (br s, 1H).

Example 3024-(4-fluoro-3-(2-oxoazepan-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 302A 4-fluoro-3-(2-oxoazepan-1-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting azepan-2-one for 5-methylpyrrolidinone. MS (DCI/NH₃)m/z 236 (M+H)⁺.

Example 302B4-(4-fluoro-3-(2-oxoazepan-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 302A for EXAMPLE 300A. MS (DCI/NH₃) m/z 370(M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ 1.54-1.65 (m, 4H),1.65-1.80 (m, 6H), 2.32-2.45 (m, 4H), 2.54-2.63 (m, 2H), 3.57-3.72 (m,2H), 3.88 (s, 2H), 7.04-7.12 (m, 2H), 7.13-7.22 (m, 1H), 12.61 (br s,1H).

Example 3031-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)piperidine-2,6-dione

The title compound was prepared according to the procedure for EXAMPLE291, substituting dihydro-2H-pyran-2,6(3H)-dione foroxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH₃) m/z 370 (M+H)⁺; ¹H NMR(300 MHz, dimethylsulfoxide-d₆): δ 1.53-1.69 (m, 4H), 1.84-1.97 (m, 1H),1.98-2.11 (m, 1H), 2.29-2.42 (m, 4H), 2.75 (t, J=6.44 Hz, 4H), 3.90 (s,2H), 7.04 (d, J=7.80 Hz, 1H), 7.24 (s, 1H), 7.26 (d, J=1.36 Hz, 1H),12.63 (s, 1H).

Example 3044-(4-fluoro-3-(2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 304A 4-fluoro-3-(2-oxoimidazolidin-1-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting imidazolidin-2-one for 5-methylpyrrolidinone. MS(DCI/NH₃) m/z 209 (M+H)⁺.

Example 304B4-(4-fluoro-3-(2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 304A for EXAMPLE 300A. MS (DCI/NH₃) m/z 343(M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d): δ 1.55-1.69 (m, 4H),2.31-2.44 (m, 4H), 3.39 (t, J=7.97 Hz, 2H), 3.75-3.83 (m, 2H), 3.86 (s,2H), 6.86 (br s, 1H), 6.94-7.03 (m, 1H), 7.16 (dd, J=1.19, 8.48 Hz, 1H),7.31 (dd, J=7.63, 2.20 Hz, 1H), 12.61 (br s, 1H).

Example 3054-(3-(1,1-dioxidoisothiazolidin-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 2 (150 mg, 0.55 mmol) in dichloromethane (5 mL)was added 3-chloropropane-1-sulfonyl chloride (97 mg, 0.55 mmol), andthe mixture stirred for 16 hours. The reaction mixture was concentrated,and the residual solid was dissolved in dioxane (3 mL). Sodium ethoxide(0.14 mL, 21 wt % in ethyl alcohol) was then added, and the solution washeated at 80° C. for 16 hours. After cooling, the reaction mixture wasconcentrated. The residue was separated by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies, Santa Clara, Calif.], 0.1%trifluoroacetic acid/CH₃CN/H₂O) to provide the title compound as freebase. MS (DCI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (300 MHz,dimethylsulfoxide-d₆): δ 1.56-1.70 (m, 4H), 2.33-2.47 (m, 6H), 3.40 (t,J=7.29 Hz, 2H), 3.72 (t, J=6.44 Hz, 2H), 3.90 (s, 2H), 7.09-7.16 (m,1H), 7.23 (d, J=8.48 Hz, 1H), 7.25-7.28 (m, 1H), 12.61 (br s, 1H).

Example 3064-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 306A 4-fluoro-3-(2-oxoazetidin-1-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting azetidin-2-one for 5-methylpyrrolidinone. MS(DCI/NH₃) m/z 194 (M+H)⁺.

Example 306B4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 306A for EXAMPLE 300A. MS (DCI/NH₃) m/z 328(M+H)⁺. ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ 1.55-1.68 (m, 4H),2.31-2.43 (m, 4H), 3.11 (t, J=4.58 Hz, 2H), 3.82 (q, J=4.41 Hz, 2H),3.86 (s, 2H), 6.86-6.94 (m, 1H), 7.18 (dd, J=11.87, 8.48 Hz, 1H), 7.74(dd, J=7.63, 2.20 Hz, 1H), 12.60 (br s, 1H).

Example 3074-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 307A 4-fluoro-3-(2-oxopiperidin-1-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting piperidin-2-one for 5-methylpyrrolidinone. MS(DCI/NH₃) m/z 222 (M+H)⁺.

Example 307B4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 307A for EXAMPLE 300A. MS (DCI/NH₃) m/z 356(M+H)⁺; ¹H NMR (300 MHz, dimethylsulfoxide-d₆): δ 1.54-1.67 (m, 4H),1.77-1.93 (m, 4H), 2.31-2.44 (m, 6H), 3.44-3.53 (m, 2H), 3.88 (s, 2H),7.10-7.14 (m, 1H), 7.15 (d, J=6.35 Hz, 1H), 7.17-7.23 (m, 1H), 12.62 (s,1H).

Example 308N-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamideExample 308A methyl3-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)benzoate

A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate(10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) indichloromethane (125 mL) was stirred at room temperature for 16 hours,and concentrated. The residue was stirred with a mixture of ethylacetate and water. The precipitated solid was filtered, washed withwater, and dried to provide the title compound. MS (DCI/NH₃) m/z 285(M+H)⁺.

Example 308B3-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)benzoicacid

A solution of EXAMPLE 308A (9.9 g, 35 mmol) in 1:1 mixture oftetrahydrofuran/water (100 mL) was treated with lithium hydroxidemonohydrate (2.93 g, 70 mmol) at room temperature for 16 hours. Ethylacetate was added (100 mL) and the mixture washed with 2M HCl (100 mL).The combined organics were concentrated and dried under vacuum toprovide the title compound. MS (DCI/NH₃) m/z 271 (M+H)⁺.

Example 308C3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoic acid

A solution of EXAMPLE 308B (9.0 g, 33.33 mmol) in absolute ethanol (120mL) was heated with hydrazine monohydrate (3.3 mL, 66.66 mmol) at 80° C.for 16 hours. After cooling to room temperature, the precipitated solidwas filtered, and dried to provide the title compound. MS (DCI/NH₃) m/z285 (M+H)⁺.

Example 308D3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl chloride

A solution of EXAMPLE 308C (2.73 g, 9.6 mmol) in anhydroustetrahydrofuran (30 mL) was treated with oxalyl chloride (1.3 mL, 14.4mmol) and a couple of drops of N,N-dimethylformamide at room temperaturefor 10 minutes and at 50° C. for 1 hour. The reaction mixture wasconcentrated and dried to provide the title compound. MS (DCI/NH₃) m/z303 (M+H)⁺.

Example 308EN-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

A solution of EXAMPLE 308D (19 mg, 0.06 mmol), furan-3-ylmethanamine(0.07 mmol) and triethylamine (14.6 mg, 0.14 mmol) in tetrahydrofuran(1.0 mL) was stirred at room temperature for 16 hours. The reactionmixture was concentrated. The residue was dissolved in 1:1 mixture ofdimethylsulfoxide/methanol and purified by HPLC (Waters Sunfire® C-8analytical column [Milford, Mass.]/0.1% trifluoroacetic acid/water/100%CH₃CN) to provide the title compound. MS (DCI/NH₃) m/z 363 (M+H)⁺; ¹HNMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ 1.54-1.69 (m, 4H), 2.32-2.45(m, 4H), 3.96 (s, 2H), 4.29 (s, 2H), 6.41-6.49 (m, 1H), 7.32-7.37 (m,1H), 7.41 (t, J=7.63 Hz, 1H), 7.52-7.60 (m, 2H), 7.64-7.72 (m, 2H).

Example 3093-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(thien-2-ylmethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting thiophen-2-ylmethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 380 (M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ1.56-1.70 (m, 4H), 2.32-2.43 (m, 4H), 3.97 (s, 2H), 4.61 (s, 2H), 6.97(dd, J=5.03, 3.51 Hz, 1H), 7.02 (d, J=2.44 Hz, 1H), 7.34-7.39 (m, 2H),7.42 (t, J=7.63 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=7.93 Hz, 1H).

Example 3103-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(thien-3-ylmethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting thiophen-3-ylmethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 380 (M+H)⁺.

Example 3113-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(pyridin-3-ylmethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting pyridin-3-ylmethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 375 (M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ1.53-1.70 (m, 4H), 2.31-2.45 (m, 4H), 3.98 (s, 2H), 4.61 (s, 2H),7.37-7.41 (m, 1H), 7.45 (t, J=7.63 Hz, 1H), 7.69 (s, 1H), 7.74 (d,J=7.63 Hz, 1H), 7.91 (dd, J=7.93, 5.49 Hz, 1H), 8.37 (d, J=7.93 Hz, 1H),8.72 (d, J=5.19 Hz, 1H), 8.78 (s, 1H).

Example 3123-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(pyridin-4-ylmethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting pyridin-4-ylmethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 375 (M+H)⁺.

Example 313N-(2-(dimethylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹,N¹-dimethylethane-1,2-diamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 355 (M+H)⁺; ¹H NMR (500 MHz,D₂O/dimethylsulfoxide-d₆): δ 1.56-1.66 (m, 4H), 2.33-2.44 (m, 4H), 2.84(s, 6H), 3.26 (t, J=5.95 Hz, 2H), 3.60 (t, J=5.95 Hz, 2H), 3.98 (s, 2H),7.38-7.41 (m, 1H), 7.45 (t, J=7.63 Hz, 1H), 7.67 (s, 1H), 7.71 (d,J=7.93 Hz, 1H).

Example 314N-(3-(dimethylamino)propyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹,N¹-dimethylpropane-1,3-diamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 369 (M+H)⁺.

Example 3153-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(3-pyrrolidin-1-ylpropyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-(pyrrolidin-1-yl)propan-1-amine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 395 (M+H)⁺.

Example 3163-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(3-piperidin-1-ylpropyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-(piperidin-1-yl)propan-1-amine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 409 (M+H)⁺.

Example 317N-(3-morpholin-4-ylpropyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-morpholinopropan-1-amine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 411 (M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆):δ 1.56-1.68 (m, 4H), 1.87-1.97 (m, 2H), 2.31-2.45 (m, 4H), 3.08 (t,J=12.05 Hz, 2H), 3.11-3.17 (m, 2H), 3.33 (t, J=6.71 Hz, 2H), 3.42 (d,J=12.51 Hz, 2H), 3.65 (t, J=12.05 Hz, 2H), 3.96-4.02 (m, 2H), 3.97 (s,2H), 7.35-7.39 (m, 1H), 7.43 (t, J=7.63 Hz, 1H), 7.65 (s, 1H), 7.69 (d,J=7.93 Hz, 1H).

Example 318N-(2-(1H-indol-3-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(1H-indol-3-yl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 427 (M+H)⁺.

Example 3193-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting thiazol-2-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR (500 MHz, D₂O/dimethylsulfoxide-d₆): δ1.59-1.68 (m, 4H), 2.35-2.46 (m, 4H), 4.01 (s, 2H), 7.28 (d, J=3.66 Hz,1H), 7.45-7.48 (m, 1H), 7.50 (t, J=7.48 Hz, 1H), 7.56 (d, J=3.66 Hz,1H), 7.87 (s, 1H), 7.93 (d, J=7.63 Hz, 1H).

Example 320 benzyl2-oxo-2-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenylamino)ethylcarbamate

The title compound was prepared according to the procedure for EXAMPLE294, substituting 2-(benzyloxycarbonylamino)acetic acid for4-oxo-4-phenylbutanoic acid. MS (DCI/NH₃) m/z 461 (M+H)⁺.

Example 3214-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)-4-(4-phenoxyphenyl)butanamide

The title compound was prepared according to the procedure for EXAMPLE294, substituting 4-oxo-4-(4-phenoxyphenyl)butanoic acid for4-oxo-4-phenylbutanoic acid. MS (DCI/NH₃) m/z 522 (M+H)⁺.

Example 322 benzyl3-(((3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate

The title compound was prepared according to the procedure for EXAMPLE294, substituting 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid for4-oxo-4-phenylbutanoic acid. MS (DCI/NH₃) m/z 515 (M+H)⁺.

Example 3232-(4-methylphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE294, substituting 2-(p-tolyloxy)acetic acid for 4-oxo-4-phenylbutanoicacid. MS (DCI/NH₃) m/z 418 (M+H)⁺.

Example 3242-(4-methoxyphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)ethyl)phenyl)acetamide

The title compound was prepared according to the procedure for EXAMPLE294, substituting 2-(4-methoxyphenoxy)acetic acid for4-oxo-4-phenylbutanoic acid. MS (DCI/NH₃) m/z 434 (M+H)⁺.

Example 3254-(4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 325A 4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting 1-methylimidazolidin-2-one for 5-methylpyrrolidinone.MS (DCI/NH₃) m/z 223 (M+H)⁺.

Example 325B4-(4-fluoro-3-(3-methyl-2-oxoimidazolidin-1-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 325A for EXAMPLE 300A. MS (DCI/H₃) m/z 357(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.54-1.69 (m, 4H), 2.32-2.43 (m,4H), 2.74 (s, 3H), 3.39-3.44 (m, 2H), 3.67-3.76 (m, 2H), 3.86 (s, 2H),6.97-7.05 (m, 1H), 7.17 (dd, J=1.19, 8.48 Hz, 1H), 7.31 (dd, J=7.63,2.20 Hz, 1H), 12.60 (s, 1H).

Example 3264-(4-fluoro-3-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 326A 4-fluoro-3-(2-oxotetrahydropyrimidin-1(2H)-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting tetrahydropyrimidin-2(1H)-one for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 223 (M+H)⁺.

Example 326B4-(4-fluoro-3-(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 326A for EXAMPLE 300A. MS (DCI/NH₃) m/z 357(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.57-1.68 (m, 4H), 1.87-2.00 (m,2H), 2.33-2.43 (m, 4H), 3.23 (t, J=5.76 Hz, 2H), 3.44-3.52 (m, 2H), 3.86(s, 2H), 6.60 (s, 1H), 7.00-7.07 (m, 1H), 7.09-7.18 (m, 2H), 12.61 (s,1H).

Example 3274-(3-(3-tert-butyl-2-oxoimidazolidin-1-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 327A3-(3-tert-butyl-2-oxoimidazolidin-1-yl)-4-fluorobenzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting 1-tert-butylimidazolidin-2-one for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 265 (M+H)⁺.

Example 327B4-(3-(3-tert-butyl-2-oxoimidazolidin-1-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 327A for EXAMPLE 300A. MS (DCI/NH₃) m/z 399(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.3 (s, 9H), 1.53-1.68 (m, 4H),2.31-2.45 (m, 4H), 3.43-3.48 (m, 2H), 3.58-3.69 (m, 2H), 3.86 (s, 2H),6.95-7.02 (m, 1H), 7.15 (dd, J=11.36, 8.31 Hz, 1H), 7.28 (dd, J=7.46,2.03 Hz, 1H), 12.59 (s, 1H).

Example 3284-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 328A4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)heptan-2-yl)benzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting (1S,4R)-2-azabicyclo(2.2.1)heptan-3-one for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 234 (M+H)⁺.

Example 328B4-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 328A for EXAMPLE 300A. MS (DCI/NH₃) m/z 368(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.49-1.56 (m, 2H), 1.57-1.65 (m,4H), 1.69-1.76 (m, 1H), 1.79-1.86 (m, 1H), 1.89-1.96 (m, 1H), 1.97-2.03(m, 1H), 2.32-2.45 (m, 4H), 2.74-2.82 (m, 1H), 3.87 (s, 2H), 4.25 (s,1H), 7.01-7.08 (m, 1H), 7.16-7.23 (m, 1H), 7.23-7.28 (m, 1H), 12.59 (brs, 1H).

Example 329N-(2-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH₃)m/z 388 (M+H)⁺.

Example 330N-(3-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH₃)m/z 388 (M+H)⁺.

Example 331N-(4-ethylphenyl)-3-((4-oxo-3,4,5,67,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-ethylaniline for furan-3-ylmethanamine. MS (DCI/NH₃)m/z 388 (M+H)⁺.

Example 3323-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-propylphenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-propylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺.

Example 333N-(2-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-isopropylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺.

Example 334N-(4-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-isopropylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.20 (d,J=7.02 Hz, 6H), 1.55-1.72 (m, 4H), 2.34-2.47 (m, 4H), 2.82-2.96 (m, 1H),4.01 (s, 2H), 7.23 (d, J=8.24 Hz, 2H), 7.39 (d, J=7.63 Hz, 1H), 7.47 (t,J=7.63 Hz, 1H), 7.63 (d, J=8.54 Hz, 2H), 7.74 (s, 1H), 7.80 (d, J=7.93Hz, 1H).

Example 335N-(3-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-tert-butylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 416 (M+H)⁺.

Example 336N-(4-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-tert-butylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 416 (M+H)⁺.

Example 337N-1,1′-biphenyl-4-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting biphenyl-4-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 436 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.57-1.70 (m,4H), 2.34-2.48 (m, 4H), 4.02 (s, 2H), 7.36 (t, J=7.32 Hz, 1H), 7.42 (d,J=7.93 Hz, 1H), 7.45-7.48 (m, 2H), 7.49-7.52 (m, 1H), 7.66-7.71 (m, 4H),7.78 (s, 1H), 7.81-7.87 (m, 3H).

Example 338N-(2-fluoro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-fluoro-4-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 392 (M+H)⁺.

Example 339N-(3-fluoro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-fluoro-4-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 392 (M+H)⁺.

Example 340N-(4-fluoro-2-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-fluoro-2-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m z 392 (M+H)⁺.

Example 341N-(4-fluoro-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-fluoro-3-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 392 (M+H)⁺.

Example 342N-(3-chloro-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-chloro-4-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 408 (M+H)⁺.

Example 343N-(4-chloro-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-chloro-3-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 408 (M+H)⁺.

Example 344N-(3-bromo-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-bromo-4-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 452 (M+H)⁺.

Example 345N-(4-bromo-3-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-bromo-3-methylaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 452 (M+H)⁺.

Example 346N-(3-fluoro-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-fluoro-4-methoxyaniline for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 408 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.55-1.69(m, 4H), 2.33-2.49 (m, 4H), 3.83 (s, 3H), 4.01 (s, 2H), 7.16 (t, J=9.31Hz, 1H), 7.40 (d, J=7.93 Hz, 1H), 7.44-7.50 (m, 2H), 7.69 (dd, J=13.58,2.59 Hz, 1H), 7.73 (s, 1H), 7.79 (d, J=7.93 Hz, 1H).

Example 347N-(3-methoxy-5-(trifluoromethyl)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-methoxy-5-(trifluoromethyl)aniline forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 458 (M+H)⁺.

Example 348N-(2-hydroxy-6-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-amino-3-methylphenol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 390 (M+H)⁺.

Example 349N-(3-hydroxy-2-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-amino-2-methylphenol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 390 (M+H)⁺.

Example 350N-(3-hydroxy-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-amino-5-methylphenol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 390 (M+H)⁺.

Example 351N-(2-methoxy-5-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-methoxy-5-methylaniline for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 352N-(3-methoxy-4-methylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 5-methoxy-2-methylaniline for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 353N-(3-hydroxy-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 5-amino-2-methoxyphenol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 406 (M+H)⁺.

Example 354N-(2-ethoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-ethoxyaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 404 (M+H)⁺.

Example 3553-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(4-propoxyphenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-propoxyaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 418 (M+H)⁺.

Example 356N-(5-tert-butyl-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 5-tert-butyl-2-methoxyaniline forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 446 (M+H)⁺.

Example 357N-(5-(acetylamino)-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N-(3-amino-4-methoxyphenyl)acetamide forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 447 (M+H)⁺.

Example 358N-2,3-dihydro-1,4-benzodioxin-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2,3-dihydrobenzo(b)(1,4)dioxin-6-amine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (500 MHz,D₂O/DMSO-d₆): δ 1.56-1.68 (m, 4H), 2.34-2.48 (m, 4H), 4.00 (s, 2H),4.15-4.32 (m, 4H), 6.84 (d, J=8.85 Hz, 1H), 7.16 (dd, J=8.85, 2.44 Hz,1H), 7.34 (d, J=2.44 Hz, 1H), 7.38 (d, J=7.93 Hz, 1H), 7.46 (t, J=7.63Hz, 1H), 7.72 (s, 1H), 7.77 (d, J=7.63 Hz, 1H).

Example 359N-(5-chloro-2,4-dimethoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 5-chloro-2,4-dimethoxyaniline forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 454 (M+H)⁺.

Example 360N-(3-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-(methylthio)aniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 406 (M+H)⁺.

Example 361N-(4-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-(methylthio)aniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 406 (M+H)⁺.

Example 3623-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(4-piperidin-1-ylphenyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-(piperidin-1-yl)aniline for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 443 (M+H)⁺.

Example 363N-(4-morpholin-4-ylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-morpholinoaniline for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 445 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.57-1.68 (m,4H), 2.34-2.46 (m, 4H), 3.15-3.23 (m, 4H), 3.79-3.82 (m, 4H), 4.01 (s,2H), 7.10 (d, J=9.15 Hz, 2H), 7.39 (d, J=7.63 Hz, 1H), 7.45-7.50 (m,1H), 7.66 (d, J=9.15 Hz, 2H), 7.72-7.77 (m, 1H), 7.80 (d, J=7.93 Hz,1H).

Example 364N-(2-anilinophenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹-phenylbenzene-1,2-diamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 451 (M+H)⁺; ¹H NMR (500 MHz,D₂O/DMSO-d₆): δ 1.54-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.95 (s, 2H), 6.78(t, J=7.32 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 7.02-7.09 (m, 1H),7.15-7.23 (m, 3H), 7.28-7.32 (m, 1H), 7.35-7.39 (m, 1H), 7.42 (t, J=7.63Hz, 1H), 7.59 (d, J=7.32 Hz, 1H), 7.63 (s, 1H), 7.69 (d, J=7.63 Hz, 1H).

Example 365N-(4-((4-methoxyphenyl)amino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹-(4-methoxyphenyl)benzene-1,2-diamine forfuran-3-ylmethanamine. MS (DCI/NH₄) m/z 481 (M+H)⁺.

Example 3663-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-quinolin-6-ylbenzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting quinolin-7-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 411 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.57-1.72 (m,4H), 2.36-2.49 (m, 4H), 4.04 (s, 2H), 7.44-7.50 (m, 1H), 7.54 (t, J=7.63Hz, 1H), 7.82 (s, 1H), 7.88 (dd, J=8.24, 5.19 Hz, 2H), 8.19 (d, J=9.15Hz, 1H), 8.27 (dd, J=9.15, 2.14 Hz, 1H), 8.74 (d, J=2.44 Hz, 1H), 8.88(d, J=7.93 Hz, 1H), 9.04 (d, J=4.88 Hz, 1H).

Example 367N-(5-hydroxy-1-naphthyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 5-aminonaphthalen-1-ol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 426 (M+H)⁺.

Example 368N-1H-indazol-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1H-indazol-6-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 400 (M+H)⁺.

Example 369 8-(4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-one Example369A methyl 2-(2-(4-fluorophenyl)acetyl)nicotinate

To a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) intetrahydrofuran (50 ml) was added (4-fluorobenzyl)magnesium chloride(0.25 M in tetrahydrofuran, 20 ml, 5.1 mmol) through a syringe at −78°C. The reaction mixture was stirred at the same temperature for 30minutes and was quenched with addition of water. After warming up toroom temperature, the reaction mixture was partitioned between ethylacetate and brine. The organic phase was washed with brine andconcentrated. The residue was purified by flash chromatography (15%ethyl acetate in hexane) to give the title compound. MS (DCI/NH₃) m/z274 (M+H)⁺.

Example 369B 8-(4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-one

A solution of EXAMPLE 369A (0.46 g, 1.68 mmol) in ethanol (20 ml) wastreated with hydrazine (108 mg, 3.37 mmol) at room temperature for 5hours. The reaction mixture was concentrated to about 5 mL. The solidwas collected by filtration, washed with ethanol and dried to providethe title compound. MS (DCI/NH₃) m/z 256 (M+H)⁺.

Example 370 8-(3-chloro-4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-oneExample 370A methyl 2-(2-(3-chloro-4-fluorophenyl)acetyl)nicotinate

The title compound was prepared according to the procedure for EXAMPLE369A, substituting (2-chloro-4-fluorobenzyl)magnesium chloride for(4-fluorobenzyl)magnesium chloride. MS (DCI/NH₃) m/z 308 (M+H)⁺.

Example 370B 8-(3-chloro-4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-one

The title compound was prepared according to the procedure for EXAMPLE369B, substituting EXAMPLE 370A for EXAMPLE 369A. MS (DCI/NH₃) m/z 290(M+H)⁺.

Example 371(3aR)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-d)(1,4)benzoxazin-1-oneExample 371A(R)-1-oxo-2,3,3a,4-tetrahydro-1H-benzo(b)pyrrolo(1,2-d)(1,4)oxazine-8-carbaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting (R)-5-(hydroxymethyl)pyrrolidin-2-one for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 232 (M+H)⁺.

Example 371B(3aR)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazin-1-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 371A for EXAMPLE 300A. MS (DCI/NH₃) m/z 352(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.54-1.63 (m, 4H), 1.64-1.72 (m,1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 1H), 2.33-2.44 (m, 4H), 2.54-2.64(m, 1H), 3.72 (t, J=10.17 Hz, 1H), 3.78-3.84 (m, 2H), 3.91-4.05 (m, 1H),4.48 (dd, J=10.51, 3.05 Hz, 1H), 6.77-6.82 (m, 1H), 6.84-6.89 (m, 1H),8.26 (d, J=2.03 Hz, 1H), 12.58 (br s, 1H).

Example 372N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N-methylmethanesulfonamideExample 372A N-(2-fluoro-5-formylphenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the procedure for EXAMPLE300A, substituting N-methylmethanesulfonamide for 5-methylpyrrolidinone.MS (DCI/NH₃) m/z 232 (M+H)⁺.

Example 372BN-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 372A for EXAMPLE 300A. MS (DCI/NH₃) m/z 366(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.57-1.71 (m, 4H), 2.34-2.47 (m,4H), 3.13 (s, 6H), 3.93 (s, 2H), 7.25 (dd, J=8.33, 1.98 Hz, 1H), 7.51(d, J=7.93 Hz, 1H), 7.58 (d, J=1.98 Hz, 1H), 12.62 (br s, 1H).

Example 373N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-hydroxy-2-methylpropanamideExample 373A N-(2-fluoro-5-formylphenyl)-2-hydroxy-2-methylpropanamide

The title compound was prepared according to the procedure for EXAMPLE300A, substituting 5,5-dimethyloxazolidine-2,4-dione for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 226 (M+H)⁺.

Example 373BN-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-hydroxy-2-methylpropanamide

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 373A for EXAMPLE 300A. MS (DCI/NH₃) m/z 360(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.34 (s, 6H), 1.53-1.70 (m, 4H),2.29-2.45 (m, 4H), 3.87 (s, 2H), 6.85-7.02 (m, 1H), 7.20 (dd, J=10.91,8.53 Hz, 1H), 7.91 (dd, J=7.54, 1.98 Hz, 1H), 9.24 (s, 1H), 12.62 (s,1H).

Example 374(3aS)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazin-1-oneExample 374A(S)-1-oxo-2,3,3a,4-tetrahydro-1H-benzo(b)pyrrolo(1,2-d)(1,4)oxazine-8-carbaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting (S)-5-(hydroxymethyl)pyrrolidin-2-one for5-methylpyrrolidinone. MS (DCI/NH₃) m/z 232 (M+H)⁺.

Example 374B(3aS)-8-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazin-1-one

The title compound was prepared according to the procedure for EXAMPLE300A, substituting EXAMPLE 374A for EXAMPLE 300B. MS (DCI/NH₃) m/z 352(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.54-1.62 (m, 4H), 1.63-1.76 (m,1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 2H), 2.32-2.40 (m, 4H), 3.72 (t,J=10.31 Hz, 1H), 3.81 (s, 2H), 3.90-4.04 (m, 1H), 4.48 (dd, J=10.71,3.17 Hz, 1H), 6.77-6.83 (m, 1H), 6.84-6.91 (m, 1H), 8.26 (d, J=1.98 Hz,1H), 12.58 (br s, 1H).

Example 3753-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-phenylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-phenylethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 388 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.56-1.69 (m,4H), 2.33-2.45 (m, 4H), 2.84 (t, J=7.48 Hz, 2H), 3.43-3.51 (m, 2H), 3.96(s, 2H), 7.21 (t, J=7.17 Hz, 1H), 7.23-7.26 (m, 2H), 7.27-7.32 (m, 2H),7.32-7.36 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.60 (s, 1H), 7.64 (d,J=7.93 Hz, 1H).

Example 376N-(2-(2-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-o-tolylethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺.

Example 377N-(2-(3-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-o-tolylethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺.

Example 378N-(2-(4-methylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-p-tolylethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺.

Example 3793-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-2-ylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 389 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.57-1.68(m, 4H), 2.31-2.43 (m, 4H), 3.24 (t, J=6.56 Hz, 2H), 3.69 (t, J=6.41 Hz,2H), 3.95 (s, 2H), 7.33-7.37 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.53 (s,1H), 7.57 (d, J=7.63 Hz, 1H), 7.86-7.89 (m, 1H), 7.90-7.94 (m, 1H),8.40-8.49 (m, 1H), 8.75 (d, J=4.88 Hz, 1H).

Example 3803-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-3-ylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 389 (M+H)⁺.

Example 3813-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-4-ylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-(pyridin-2-yl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 389 (M+H)⁺.

Example 382N-(2-(2-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2-methoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 418 (M+H)⁺.

Example 383N-(2-(3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 3-(2-methoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 418 (M+H)⁺.

Example 384N-(2-(4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 4-(2-methoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (500 MHz,D₂O/DMSO-d₆): δ 1.55-1.68 (m, 4H), 2.32-2.45 (m, 4H), 2.77 (t, J=7.48Hz, 2H), 3.37-3.47 (m, 2H), 3.71 (s, 3H), 3.96 (s, 2H), 6.83-6.88 (m,2H), 7.14-7.20 (m, 2H), 7.32-7.36 (m, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.61(s, 1H), 7.64 (d, J=7.63 Hz, 1H).

Example 385N-(2-(2-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2-fluorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 406 (M+H)⁺.

Example 386N-(2-(3-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3-fluorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 406 (M+H)⁺.

Example 387N-(2-(4-fluorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-fluorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 406 (M+H)⁺.

Example 388N-(2-(2-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2-chlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 389N-(2-(3-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3-chlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 390N-(2-(4-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-chlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 391N-(2-(3-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3-bromophenyl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 467 (M+H)⁺.

Example 392N-(2-(4-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-bromophenyl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 467 (M+H)⁺.

Example 393N-(2-(1,1′-biphenyl-4-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(biphenyl-4-yl)ethanamine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 464 (M+H)⁺; ¹H NMR (500 MHz, D₂O/DMSO-d₆): δ 1.54-1.67(m, 4H), 2.30-2.44 (m, 4H), 2.89 (t, J=7.48 Hz, 2H), 3.52 (t, J=7.32 Hz,2H), 3.96 (s, 2H), 7.33-7.37 (m, 4H), 7.41 (t, J=7.63 Hz, 1H), 7.44-7.50(m, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.64 (d, J=8.24 Hz, 2H), 7.64-7.68 (m,2H).

Example 3943-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-(3-(trifluoromethyl)phenyl)ethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3-(trifluoromethyl)phenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 456 (M+H)⁺.

Example 3953-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-(4-(trifluoromethyl)phenyl)ethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-(trifluoromethyl)phenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 456 (M+H)⁺.

Example 3963-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-(4-phenoxyphenyl)ethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-phenoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 480 (M+H)⁺; ¹H NMR (500 MHz,D₂O/DMSO-d₆): δ 1.55-1.66 (m, 4H), 2.32-2.43 (m, 4H), 2.83 (t, J=7.32Hz, 2H), 3.48 (t, J=7.32 Hz, 2H), 3.96 (s, 2H), 6.91-6.94 (m, 2H), 6.96(d, J=7.63 Hz, 2H), 7.12 (t, J=7.48 Hz, 1H), 7.26 (d, J=8.54 Hz, 2H),7.32-7.35 (m, 1H), 7.35-7.38 (m, 2H), 7.38-7.43 (m, 1H), 7.62 (s, 1H),7.64 (d, J=7.63 Hz, 1H).

Example 397N-(2-(3,4-dimethylphenyl)ethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,78-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3,4-dimethylphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 416 (M+H)⁺.

Example 398N-(2-(2,4-dimethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,4-dimethylphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 416 (M+H)⁺.

Example 399N-(2-(2,5-dimethylphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,5-dimethylphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 416 (M+H)⁺.

Example 400N-(2-(3-ethoxy-4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3-ethoxy-4-methoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 462 (M+H)⁺.

Example 401N-(2-(4-ethoxy-3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(4-ethoxy-3-methoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 462 (M+H)⁺.

Example 402N-(2-(2,3-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,3-dimethoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 403N-(2-(2,4-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,4-dimethoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 404N-(2-(2,5-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,5-dimethoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 405N-(2-(3,4-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3,4-dimethoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 406N-(2-(3,5-dimethoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3,5-dimethoxyphenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 448 (M+H)⁺.

Example 407N-(2-(1,3-benzodioxol-5-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(benzo(d)(1,3)dioxol-5-yl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 432 (M+H)⁺; ¹H NMR (500 MHz,D₂O/DMSO-d₆): δ 1.54-1.72 (m, 4H), 2.32-2.44 (m, 4H), 2.75 (t, J=7.32Hz, 2H), 3.43 (t, J=7.32 Hz, 2H), 3.96 (s, 2H), 5.94 (s, 2H), 6.70 (dd,J=7.93, 1.53 Hz, 1H), 6.80 (s, 1H), 6.81-6.83 (m, 1H), 7.32-7.36 (m,1H), 7.40 (t, J=7.63 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=17.93 Hz, 1H).

Example 408N-(2-(2,3-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,3-dichlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 457 (M+H)⁺.

Example 409N-(2-(3,4-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3,4-dichlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 457 (M+H)⁺.

Example 410N-(2-(2,6-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2,6-dichlorophenyl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 457 (M+H)⁺.

Example 411(3aS,4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-dimethyltetrahydro-4,7-methano(1,3)dioxolo(4,5-c)pyridin-6(3aH)-oneExample 411A3-((3aS,4R,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4,7-methano(1,3)dioxolo(4,5-c)pyridin-5(4H)-yl)-4-fluorobenzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting(1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo(5.2.1.0(2,6))decan-9-onefor 5-methylpyrrolidinone. MS (DCI/NH₃) m/z 306 (M+H)⁺.

Example 411B(3aS,4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,2-dimethyltetrahydro-4,7-methano(1,3)dioxolo(4,5-c)pyridin-6(3aH)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 411A for EXAMPLE 300B. MS (DCI/NH₃) m/z 440(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.29-1.34 (m, 3H), 1.42 (s, 3H),1.55-1.67 (m, 4H), 2.01-2.11 (m, 1H), 2.12-2.21 (m, 1H), 2.32-2.45 (m,4H), 2.77-2.84 (m, 1H), 3.88 (s, 2H), 4.16-4.24 (m, 1H), 4.58-4.64 (m,1H), 4.64-4.69 (m, 1H), 7.02-7.09 (m, 1H), 7.22 (dd, J=11.19, 8.48 Hz,1H), 7.31 (dd, J=7.46, 2.03 Hz, 1H), 12.59 (s, 1H).

Example 4124-(1-(3-bromo-4-fluorophenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 412A 1-(3-bromo-4-fluorophenyl)ethanol

A solution of 1-(3-bromo-4-fluorophenyl)ethanone (15.0 g, 69 mmol) intetrahydrofuran (200 mL) was treated with sodium borohydride (5.3 g, 138mmol) at 0° C.

After the addition, the ice bath was removed, and the mixture wasstirred at room temperature for 30 minutes and at reflux overnight.After cooling, 1N HCl (10 mL) was slowly added and the reaction mixturewas concentrated. The residue was partitioned between ethyl acetate andbrine. The organic phase was washed with water, and concentrated. Theresidue was purified by flash chromatography (30% ethyl acetate inhexane) to provide the title compound. MS (DCI/NH₃) m/z 220 (M+H)⁺.

Example 412B 2-bromo-4-(1-bromoethyl)-1-fluorobenzene

To a solution of EXAMPLE 412A (1.5 g, 6.8 mmol) and triphenyl phosphine(1.9 g, 7.2 mmol) in dimethylformamide (20 ml) was added bromine (1.1 g,6.8 mmol) through a syringe. After the addition, the reaction mixturewas stirred at room temperature for additional 15 minutes, andpartitioned between water (100 ml) and ethyl acetate (200 ml). Theorganic phase was washed with brine and concentrated. The residue waspurified by flash chromatography (2.6% ethyl acetate in hexane) toprovide the title compound. MS (DCI/NH₄) m/z 282 (M+H)⁺.

Example 412C

(1-(3-bromo-4-fluorophenyl)ethyl)triphenylphosphonium bromide

The title compound was prepared according to the procedure for EXAMPLE285B, substituting EXAMPLE 412B for EXAMPLE 285A.

Example 412D3-(1-(3-bromo-4-fluorophenyl)ethylidene)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

The title compound was prepared according to the procedure for EXAMPLE285C, substituting EXAMPLE 412C for EXAMPLE 285B. MS (DCI/NH₃) m/z 338(M+H)⁺.

Example 412E 4-(1-(3-bromophenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE2C, substituting EXAMPLE 412D for EXAMPLE 2B. MS (DCI/NH₃) m/z 352(M+H)⁺.

Example 4134-(1-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 412 for EXAMPLE 103, and pyrroline-2-one forazetidin-2-one. MS (ESI) m/z 356 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.42 (d, J=6.74 Hz, 3H), 1.46-1.70 (m, 4H), 1.93-2.16 (m, 4H), 2.29-2.67(m, 6H), 4.25 (q, J=6.74 Hz, 1H), 7.07-7.15 (m, 1H), 7.18 (s, 1H),7.19-7.29 (m, 1H), 12.70 (s, 1H).

Example 4148-(4-fluorobenzyl)-1,2,3,4-tetrahydropyrido(3,2-d)pyridazin-5(6H)-one

A mixture of EXAMPLE 369 (150 mg, 0.6 mmol), 5% platinum on carbon (30mg), concentrated aqueous HCl (50 μL) and dimethylformamide (5 ml) in apressure vessel was stirred at room temperature under 50 psi of hydrogenfor 16 hours. The mixture was filtered, and the filtrate wasconcentrated. The residual solid was purified by HPLC (Zorbax® C-18 ODSpacking material [Agilent Technologies. Santa Clara, Calif.], 0.1%TFA/CH₃CNH₂O) to provide the title product as TFA salt. MS (EST) m/z 260(M+H)⁺.

Example 415 8-(3-bromo-4-fluorobenzyl)pyrido(3,2-d pyridazin-5(6H)-oneExample 415A methyl 2-(2-(3-bromo-4-fluorophenyl)acetyl)nicotinate

A mixture of magnesium turnings (880 mg, 37 mmol) and2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrousdiethyl ether (15 ml) was treated with a piece of iodine. The mixturewas then heated to gentle reflux until the color of the mixturedisappeared, after which the heating continued for additional hour. Thesuspension was cooled to room temperature, and cannulated into asolution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) intetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintainedat the same temperature for 30 minutes, and was quenched with additionof water. After warming up to room temperature, the reaction mixture waspartitioned between ethyl acetate and brine. The organic phase waswashed with brine and concentrated. The residue was purified by flashchromatography (15% ethyl acetate in hexane) to provide the titlecompound. MS (DCI/NH₃) m/z 353 (M+H)⁺.

Example 415B 8-(3-bromo-4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-one

The title compound was prepared according to the procedure for EXAMPLE369B substituting EXAMPLE 415A for EXAMPLE 369A. MS (DCI/NH₃) m/z 335(M+H)⁺.

Example 418N-(2-(dimethylamino)ethyl)-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹-ethyl-N²,N²-dimethylethane-1,2-diamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 383 (M+H)⁺.

Example 419N-(2-(diethylamino)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N¹,N¹-diethyl-N²-methylethane-1,2-diamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 397 (M+H)⁺.

Example 420N-benzyl-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N-benzylethanamine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 0.97-1.11(m, 3H), 1.36-1.57 (m, 4H), 2.22-2.30 (m, 2H), 2.50-2.66 (m, 2H),3.27-3.45 (m, 2H), 3.98 (s, 2H), 4.61-4.74 (m, 2H), 7.26-7.31 (m, 1H),7.32-7.40 (m, 6H), 7.42-7.47 (m, 1H), 7.52 (s, 1H).

Example 421N-benzyl-N-isopropyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N-benzylpropan-2-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 416 (M+H)⁺.

Example 422N-benzyl-N-butyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N-benzylbutan-1-amine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 430 (M+H)⁺.

Example 423N,N-dibenzyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting dibenzylamine for furan-3-ylmethanamine. MS (DCI/NH₃)m/z 464 (M+H)⁺.

Example 424N-benzyl-N-(2-hydroxyethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(benzylamino)ethanol for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 418 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 1.40-1.54(m, 4H), 2.21-2.33 (m, 2H), 2.50-2.61 (m, 2H), 3.62-3.78 (m, 2H),3.89-4.02 (m, 2H), 3.96 (s, 2H), 4.82-4.97 (m, 2H), 7.25-7.29 (m, 1H),7.30-7.36 (m, 5H), 7.36-7.43 (m, 1H), 7.43-7.47 (m, 1H), 7.50 (d, J=7.32Hz, 1H).

Example 426N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)-N-(2-pyridin-2-ylethyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting N-methyl-2-(pyridin-2-yl)ethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 403 (M+H)⁺; ¹H NMR (500 MHz,D₂O/pyridine-d₅): δ 1.42-1.52 (m, 4H), 2.24-2.34 (m, 2H), 2.51-2.62 (m,2H), 2.97 (s, 3H), 3.07-3.21 (m, 2H), 3.83-3.94 (m, 2H), 3.99 (s, 2H),7.12 (dd, J=7.32, 5.49 Hz, 1H), 7.14-7.20 (m, 1H), 7.28-7.32 (m, 2H),7.32-7.37 (m, 1H), 7.37-7.45 (m, 1H), 7.57 (t, J=7.63 Hz, 1H), 8.55 (d,J=3.66 Hz, 1H).

Example 427N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(3,4-dimethoxyphenyl)-N-methylethanamine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 462 (M+H)⁺.

Example 4284-(3-((4-hydroxypiperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting piperidin-4-ol for furan-3-ylmethanamine. MS (DCI/NH₃)m/z 368 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 1.42-1.52 (m, 4H),1.63-1.75 (m, 2H), 1.87-1.98 (m, 2H), 2.27-2.35 (m, 2H), 2.54-2.62 (m,2H), 3.25-3.40 (m, 2H), 4.01 (s, 2H), 4.01-4.04 (m, 2H), 4.05-4.07 (m,1H), 7.35 (t, J=7.17 Hz, 1H), 7.37-7.40 (m, 1H), 7.40-7.44 (m, 1H), 7.51(s, 1H).

Example 4291-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperidine-3-carboxamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting piperidine-3-carboxamide for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 395 (M+H)⁺.

Example 4301-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperidine-4-carboxamide

The title compound was prepared according to the procedure for EXAMPLE308, substituting piperidine-4-carboxamide for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 1.41-1.55(m, 4H), 1.82-1.97 (m, 4H), 2.27-2.37 (m, 2H), 2.54-2.61 (m, 2H),2.63-2.73 (m, 1H), 2.94-3.06 (m, 2H), 4.00 (s, 2H), 4.16-4.32 (m, 2H),7.32-7.36 (m, 1H), 7.36-7.40 (m, 2H), 7.48-7.51 (m, 1H).

Example 4344-(3-((4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(piperidin-4-yl)-1H-benzo(d)imidazol-2(3H)-one forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 484 (M+H)⁺.

Example 4354-(3-((4-methylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-methylpiperazine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 1.46-1.52(m, 4H), 2.24 (s, 3H), 2.29-2.34 (m, 2H), 2.37-2.42 (m, 4H), 2.54-2.62(m, 2H), 3.61-3.73 (m, 4H), 4.02 (s, 2H), 7.35-7.39 (m, 1H), 7.39-7.43(m, 2H), 7.51 (s, 1H).

Example 4364-(3-((4-ethylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-ethylpiperazine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 381 (M+H)⁺.

Example 4374-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbaldehyde

The title compound was prepared according to the procedure for EXAMPLE308, substituting piperazine-1-carbaldehyde for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 381 (M+H)⁺.

Example 4384-(3-((4-acetylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(piperazin-1-yl)ethanone for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 395 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ1.44-1.57 (m, 4H), 2.09 (s, 3H), 2.28-2.39 (m, 2H), 2.51-2.66 (m, 2H),3.39-3.73 (m, 8H), 4.03 (s, 2H), 7.36-7.39 (m, 1H), 7.43 (t, J=7.02 Hz,2H), 7.54 (s, 1H).

Example 4394-(3-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(piperazin-1-yl)ethanol for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 397 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ1.42-1.55 (m, 4H), 2.27-2.37 (m, 2H), 2.50-2.62 (m, 6H), 2.69 (t, J=5.80Hz, 2H), 3.54-3.75 (m, 4H), 3.89 (t, J=5.80 Hz, 2H), 4.02 (s, 2H),7.35-7.38 (m, 1H), 7.39-7.43 (m, 2H), 7.50 (s, 1H).

Example 4404-(3-((4-phenylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-phenylpiperazine for furan-3-ylmethanamine. MS(DCI/NH₃) m/z 429 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ 1.44-1.57(m, 4H), 2.27-2.42 (m, 2H), 2.52-2.66 (m, 2H), 3.08-3.20 (m, 4H),3.68-3.83 (m, 4H), 4.04 (s, 2H), 6.91 (t, J=7.32 Hz, 1H), 6.98 (d,J=7.93 Hz, 2H), 7.28-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t, J=7.48Hz, 1H), 7.46-7.49 (m, 1H), 7.57 (s, 1H).

Example 4414-(3-((4-pyridin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(pyridin-2-yl)piperazine for furan-3-ylmethanamine.MS (DCI/NH₃) m/z 430 (M+H)⁺; ¹H NMR (500 MHz, D₂O/pyridine-d₅): δ1.46-1.55 (m, 4H), 2.29-2.40 (m, 2H), 2.52-2.65 (m, 2H), 3.53-3.63 (m,4H), 3.64-3.78 (m, 4H), 4.03 (s, 2H), 6.66 (dd, J=6.71, 4.58 Hz, 1H),6.73 (d, J=8.54 Hz, 1H), 7.37-7.41 (m, 1H), 7.43 (d, J=7.63 Hz, 1H),7.45-7.48 (m, 1H), 7.49-7.54 (m, 1H), 7.57 (s, 1H), 8.29 (dd, J=4.88,1.22 Hz, 1H).

Example 4424-(3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(piperazin-1-yl)pyrimidine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 431 (M+H)⁺; ¹H NMR (500 MHz,D₂O/pyridine-d₅): δ 1.42-1.59 (m, 4H), 2.26-2.40 (m, 2H), 2.50-2.66 (m,2H), 3.62-3.74 (m, 4H), 3.82-3.91 (m, 4H), 4.03 (s, 2H), 6.55 (t, J=4.73Hz, 1H), 7.38 (d, J=5.80 Hz, 1H), 7.40-7.45 (m, 1H), 7.45-7.49 (m, 1H),7.57 (s, 1H), 8.38 (d, J=4.88 Hz, 2H).

Example 4434-(3-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 2-(2-(piperazin-1-yl)ethoxy)ethanol forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 441 (M+H)⁺.

Example 4444-(3-((4-(2-fluorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(2-fluorophenyl)piperazine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 447 (M+H)⁺.

Example 4454-(3-((4-(4-fluorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(4-fluorophenyl)piperazine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 447 (M+H)⁺; ¹H NMR (500 MHz,D₂O/pyridine-d₅): δ 1.44-1.56 (m, 4H), 2.30-2.39 (m, 2H), 2.53-2.63 (m,2H), 3.02-3.12 (m, 4H), 3.68-3.81 (m, 4H), 4.05 (s, 2H), 6.93-6.97 (m,2H), 7.04-7.09 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t, J=7.32 Hz, 1H),7.46-7.51 (m, 1H), 7.57 (s, 1H).

Example 4464-(3-((4-(2-chlorophenyl)piperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-(2-chlorophenyl)piperazine forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 463 (M+H)⁺.

Example 4474-(3-((4-methyl-1,4-diazepan-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE308, substituting 1-methyl-4-(piperazin-1-yl)azepane forfuran-3-ylmethanamine. MS (DCI/NH₃) m/z 381 (M+H)⁺; ¹H NMR (500 MHz,D₂O/pyridine-d₅): δ 1.44-1.48 (m, 1H), 1.48-1.51 (m, 4H), 1.92-2.01 (m,2H), 2.28-2.36 (m, 2H), 2.51-2.55 (m, 2H), 2.58 (s, 3H), 2.64 (t, J=5.65Hz, 1H), 2.84-2.94 (m, 2H), 3.64-3.71 (m, 3H), 3.88-3.92 (m, 1H), 4.01(s, 2H), 7.33-7.39 (m, 1H), 7.39-7.41 (m, 1H), 7.41-7.45 (m, 1H), 7.51(s, 1H).

Example 4484-(3-(1-dioxido-1,2-thiazinan-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 448A 3-(1,1-dioxido-1,2-thiazinan-2-yl)-4-fluorobenzaldehyde

The title compound was prepared according to the procedure for EXAMPLE300A, substituting 1,4-butanesultam for 5-methylpyrrolidinone. MS(DCI/NH₃) m/z 258 (M+H)⁺.

Example 448B4-(3-(1,1-dioxido-1,2-thiazinan-2-yl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 448A for EXAMPLE 300A. MS (DCI/NH₃) m/z 392(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.57-1.71 (m, 4H), 1.75-1.87 (m,2H), 2.13-2.24 (m, 2H), 2.34-2.46 (m, 4H), 3.16-3.28 (m, 2H), 3.46-3.58(m, 2H), 3.92 (s, 2H), 7.23 (dd, J=8.13, 2.18 Hz, 1H), 7.48 (d, J=7.93Hz, 1H), 7.57 (d, J=1.59 Hz, 1H), 12.61 (br s, 1H).

Example 4498-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)pyrido(2,3-d)pyridazin-5(6H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 415 for EXAMPLE 103. MS (ESI) m/z 325 (M+H)⁺.

Example 4508-(3-chloro-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one

The title compound was prepared as TFA salt according to procedure forEXAMPLE 414, substituting EXAMPLE 370 for EXAMPLE 369. MS (ESI) m/z 294(M+H)⁺.

Example 4514-(1-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 412 for EXAMPLE 103. MS (ESI) m/z 342 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): 1.41 (d, J=7.12 Hz, 3H), 1.44-1.67 (m, 4H),1.84-2.08 (m, 1H), 2.34 (m, 2H), 2.53-2.74 (m, 1H), 3.11 (t, J=4.58 Hz,2H), 3.72-3.88 (m, 2H), 4.22 (q, J=6.78 Hz, 1H), 6.81-6.95 (m, 1H), 7.18(dd, J=11.87, 8.48 Hz, 1H), 7.76 (dd, J=7.46, 2.37 Hz, 1H), 12.70 (s,1H).

Example 4521-(3-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione

The title compound was prepared according to the procedure for EXAMPLEs2, 3 and 4, substituting 3-nitrobenzaldehyde for4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH₃) m/z 256 (M+H)⁺.

Example 453N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2-(2-oxopyrrolidin-1-yl)acetamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and2-(2-oxopyrrolidin-1-yl)acetic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 356 (M+H)⁺. MS (DCI/NH₃) m/z 399 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆): δ 1.53-1.67 (m, 4H), 1.89-2.06 (m, 2H), 2.26 (t,J=7.97 Hz, 2H), 2.31-2.43 (m, 4H), 3.39-3.47 (m, 2H), 3.86 (s, 2H), 4.07(s, 2H), 6.93-6.99 (m, 1H), 7.18 (dd, J=10.85, 8.48 Hz, 1H), 7.71 (dd,J=7.46, 2.03 Hz, 1H), 9.82 (br s, 1H), 12.61 (br s, 1H).

Example 454N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid for1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃) m/z 356 (M+H)⁺. MS(DCI/NH₃) m/z 458 (M+H)⁺.

Example 455N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-5-oxohexanamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and5-oxohexanoic acid for 1-methylcyclopropanecarboxylic acid. MS (DCI/NH₃)m/z 386 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.53-1.65 (m, 4H),1.67-1.80 (m, 2H), 2.08 (s, 3H), 2.28-2.34 (m, 2H), 2.34-2.41 (m, 4H),2.42-2.49 (m, 2H), 3.85 (s, 2H), 6.82-6.96 (m, 1H), 7.15 (dd, J=10.85,8.48 Hz, 1H), 7.67 (dd, J=7.46, 1.70 Hz, 1H), 9.60 (br s, 1H), 12.61 (brs, 1H).

Example 456N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-3-methoxypropanamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and3-methoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS(DCI/NH₃) m/z 360 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.55-1.66 (m,4H), 2.30-2.43 (m, 4H), 2.60 (t, J=6.10 Hz, 2H), 3.23 (s, 3H), 3.59 (t,J=6.27 Hz, 2H), 3.86 (s, 2H), 6.85-6.99 (m, 1H), 7.16 (dd, J=10.85, 8.48Hz, 1H), 7.74 (dd, J=7.46, 1.70 Hz, 1H), 9.64 (br s, 1H), 12.61 (br s,1H).

Example 457N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N′-phenylpentanediamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 2 for EXAMPLE 89, and5-oxo-5-(phenylamino)pentanoic acid for 1-methylcyclopropanecarboxylicacid. MS (DCI/NH₃) m/z 463 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.55-1.67 (m, 4H), 1.83-1.94 (m, 2H), 2.31-2.40 (m, 6H), 2.40-2.45 (m,2H), 3.85 (s, 2H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.15 (dd,J=10.85, 8.48 Hz, 1H), 7.24-7.32 (m, 2H), 7.59 (d, J=7.46 Hz, 2H), 7.71(dd, J=7.97, 1.53 Hz, 1H), 9.67 (br s, 1H), 9.88 (br s, 1H), 12.62 (brs, 1H).

Example 458 benzyl2-(dimethylamino)-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylcarbamateExample 458A 4-(dimethylamino)-N-methoxy-N-methyl-3-nitrobenzamide

To a solution of 4-fluoro-3-nitrobenzoic acid (5 g, 27.0 mmol) indimethylformamide (100 mL) was added N,O-dimethylhydroxylaminehydrochloride (5.93 g, 60.8 mmol) and triethylamine (17.0 mL, 122 mmol).1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (11.65 g,60.8 mmol) and hydroxybenzotriazole (9.31 g, 60.8 mmol) were added andthe reaction mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated and partitioned between ethyl acetate(150 mL) and brine (150 mL). The organics were concentrated on rotaryevaporator and the crude was purified by flash chromatography elutingwith 40% ethyl acetate in hexanes to provide the title product. MS(DCI/NH₃) m/z 254 (M+H)⁺.

Example 458B 3-amino-4-(dimethylamino)-N-methoxy-N-methylbenzamide

A solution of EXAMPLE 458A (2.34 g, 9.24 mmol) in tetrahydrofuran (40mL) was treated with Raney Ni (2.0 g, Raney 2800, slurry in water) atroom temperature under a hydrogen (balloon) for 16 hours. The catalystwas filtered off, and the filtrate was concentrated. The residue wasused the subsequent step without further purification.

Example 458C benzyl2-(dimethylamino)-5-(methoxy(methyl)carbamoyl)phenylcarbamate

To a solution of EXAMPLE 458B in a mixture of tetrahydrofuran (20 mL)and water (20 mL) was added cesium carbonate (6.02 g, 18.58 mmol) andbenzyl chloroformate (1.5 mL, 10.16 mmol). The reaction mixture wasstirred at room temperature for 16 hours, and concentrated. The residuewas partitioned between ethyl acetate (100 mL) and brine (75 mL). Theorganic layer was washed with brine, and concentrated. The residual oilwas purified by flash chromatography eluting with 40% ethyl acetate inhexanes to provide the title product. MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 458D benzyl 2-(dimethylamino)-5-formylphenylcarbamate

A solution of EXAMPLE 458C (2.89 g, 8.1 mmol) in anhydroustetrahydrofuran (20 mL) was treated with lithium aluminum hydride (1.0 Msolution in tetrahydrofuran, 8.1 mL, 8.1 mmol) at 0° C. for 10 minutes.The reaction was quenched with water, and the mixture was partitionedbetween ethyl acetate and diluted HCl solution. The organic layer waswashed with brine, and concentrated on a rotary evaporator. The residualoil was purified by flash chromatography eluting with 20% ethyl acetatein hexanes to provide the title product. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 458E benzyl2-(dimethylamino)-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylcarbamate

The title compound was prepared according to the procedure for EXAMPLE300B, substituting EXAMPLE 458D for EXAMPLE 300A. MS (DCI/NH₃) m/z 433(M+H)¹.

Example 4598-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-1,2,3,4-tetrahydropyrido(3,2-d)pyridazin-5(6H)-one

The title compound was prepared according to procedure for EXAMPLE 414,substituting EXAMPLE 449 for EXAMPLE 369. MS (EST) m/z 329 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 1.61-1.76 (m, 2H), 2.33 (t, J=6.35 Hz, 2H),3.12 (t, J=4.56 Hz, 2H), 3.17 (m, 2H), 3.77 (s, 2H), 3.81 (q, J=4.36 Hz,2H), 6.32 (s, 1H), 6.87-7.01 (m, 1H), 7.17 (dd, J=11.90, 8.33 Hz, 1H),7.78 (dd, J=7.54, 2.38 Hz, 1H), 11.80 (s, 1H).

Example 4604-(3-bromo-4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 460A3-(3-bromo-4-fluorophenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

To a solution of 2-bromo-1-fluoro-4-iodobenzene (13.23 g, 44 mmol) inanhydrous tetrahydrofuran (30 mL) was added isopropylmagnesium chloride(2.0 M solution in tetrahydrofuran, 24.18 mL, 48.4 mmol) at −20° C.After the addition, the reaction mixture was stirred at 0° C. for 3hours, and was added to a solution of 3,4,5,6-tetrahydrophthalicanhydride (6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) at −78°C. The mixture was stirred for 2 hours, and a saturated aqueous ammoniumchloride solution was added to the reaction mixture, which then wasstirred at room temperature for 30 minutes. Anhydrous magnesium sulfatewas added to the reaction mixture, and the mixture was filtered. Thefiltrate was concentrated. Thionyl chloride (10.4 mL, 142 mol) was addeddropwise to methanol (40 mL) at −10° C., and the solution was stirred at0° C. for 30 minutes. To the thionyl chloride solution was then addedthe residue from the filtrate in anhydrous methanol (15 mL). Thereaction mixture was stirred at room temperature overnight, and wasconcentrated. The residue was dissolved in methylene chloride (40 mL),and was treated with triethylamine (5.58 mL) at 0° C. for 1 hour. Waterwas added, and the mixture was washed with sodium bicarbonate, brine andwater. The organic phase was dried over magnesium sulfate, filtered andconcentrated. The residue was separated by flash chromatography (10-35%gradient ethyl acetate in hexane) to provide the title compound. MS(DCI/NH₃) m/z 341, 343 (M+H)⁺.

Example 460B4-(3-bromo-4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 460A (9.5 g, 27.8 mmol) and hydrazine monohydrate(1.76 mL, 36.2 mmol) in ethanol (70 mL) was heated under reflux for 4hours. After cooling to room temperature, the solids were collected byfiltration, washed with ethanol and dried to provide the title compound.MS (DCI/NH₃) m/z 323, 325 (M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆): δ 1.57-1.65(m, 2H), 1.66-1.74 (m, 2H), 2.34 (t, J=5.75 Hz, 2H), 2.45 (t, J=6.15 Hz,2H), 7.45 (t, J=8.72 Hz, 1H), 7.49-7.55 (m, 1H), 7.80 (dd, J=6.74, 2.38Hz, 1H), 12.85 (br s, 1H).

Example 4614-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 461A2-(benzyloxymethyl)-4-(3-bromo-4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 460 (2.0 g, 6.19 mmol) in anhydrousdimethylformamide (30 mL) was added potassium t-butoxide (1 M solutionin tetrahydrofuran, 6.50 mL, 6.5 mmol). The solution was stirred at roomtemperature for 30 minutes, and benzyl chloromethylether (1.163 g, 7.43mmol) was added. The reaction mixture was stirred at room temperatureovernight. After quenching with water, the reaction mixture waspartitioned between water and ethyl acetate. The organic phase waswashed with water, and concentrated. The residue was separated by flashchromatography (20-60% gradient ethyl acetate in hexane) to provide thetitle compound. MS (DCI/NH₃) m/z 443 (M+H)⁺.

Example 461B2-(benzyloxymethyl)-4-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A microwave reactor tube was charged with EXAMPLE 461A (137 mg, 0.309mmol), tris(dibenzylideneacetone)dipalladium(0) (28.3 mg, 0.031 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26.9 mg,0.046 mmol), 2-azetidinone (44 mg, 0.619 mmol), and potassium phosphatetribasic (98 mg, 0.464 mmol). Anhydrous dioxane (3 mL) was added. Thesuspension was purged with nitrogen, and was capped with a microwaveseptum. The reaction mixture was heated in a CEM Explorer® microwavereactor (Matthews, N.C.) at 200° C. for 50 minutes. After cooling, thereaction mixture was partitioned between ethyl acetate and brine. Theorganic phase was washed with water, and concentrated. The residue wasseparated by flash chromatography (20-70% gradient ethyl acetate inhexane) to provide the title compound. MS (DCI/NH₃) m/z 434 (M+H)⁺.

Example 461C4-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 461B (140 mg, 0.323 mmol) in methanol (10 mL)was added 20% palladium hydroxide on carbon (80 mg) under nitrogen. Thissuspension was purged with hydrogen, and stirred under hydrogen(balloon) at 50° C. for 4 hours. The mixture was filtered, and thefiltrate was concentrated. The residue was recrystallized from methanol(4 mL) to provide the title compound. The mother liquor was separated byHPLC (Zorbax® C-18 ODS packing material [Agilent Technologies. SantaClara, Calif.), 250×2.54 column. Mobile phase A: 0.1% TFA in H₂O; B:0.1% TFA in CH₃CN; 0-100% gradient) to provide additional titlecompound. MS (DCI/NH₃) m/z 314 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆), δ1.57-1.63 (m, 2H), 1.67-1.74 (m, 2H), 2.33 (t, J=5.83 Hz, 2H), 2.45 (t,J=6.14 Hz, 2H), 3.14-3.18 (m, 2H), 3.86-3.90 (m, 2H), 7.16-7.21 (m, 1H),7.34 (dd, J=11.66, 8.59 Hz, 1H), 7.93 (dd, J=7.52, 2.30 Hz, 1H), 12.89(s, 1H).

Example 4622-fluoro-5-((5-oxo-5,6-dihydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamideExample 462A methyl2-fluoro-5-((5-oxo-5,6-dihydropyrido(3,2-d)pyridazin-8-yl)methyl)benzoate

The title compound was prepared according to the procedure for EXAMPLE66C, substituting EXAMPLE 415 for EXAMPLE 66B. MS (DCI/NH₃) m/z 314(M+H)⁺.

Example 462B2-fluoro-5-((5-oxo-5,6-dihydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide

A solution of EXAMPLE 462A (1 g, 3.2 mmol) in 7N ammonia in methanol (5ml) was heated at 70° C. overnight, and cooled to room temperature. Thesolid was collected by filtration, washed with methanol and dried toprovide the title compound. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 463 8-(3-amino-4-fluorobenzyl)pyrido(2,3-d)pyridazin-5(6H)-one

A mixture of 1.5 N aqueous KOH solution (2 ml) and 3 g of ice wastreated with bromine (80 mg, 0.5 mmol) at −10° C. for 10 minutes.EXAMPLE 462 (100 mg, 0.3 mmol) was added. The reaction mixture wasstirred at −10° C. for an additional 10 minutes, and was then allowed towarm up to 65° C. for 1 hour. After cooling, the mixture was partitionedbetween ethyl acetate and brine. The organic phase was washed withbrine, and concentrated to about 10 mL. The solid was collected byfiltration, washed with methanol, and dried to provide the titlecompound. MS (DCI/NH₃) m/z 271 (M+H)⁺.

Example 4648-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-oneExample 464A6-(benzyloxymethyl)-8-(3-bromo-4-fluorobenzyl)pyrido(3,2-d)pyridazin-5(6H)-one

A solution of EXAMPLE 415 (1 g, 3 mmol) in anhydrous dimethylformamide(100 ml) was treated with potassium t-butoxide (1N solution intetrahydrofuran, 3 mL, 3 mmol) at room temperature for 30 minutes.Benzyloxychloromethane (0.6 g, 3.6 mmol) was then added, and the mixturewas stirred at room temperature overnight. After quenching with water,the reaction mixture was partitioned between ethyl acetate and brine.The organic layer was washed with brine, and concentrated. The residuewas purified by flash chromatography (85% ethyl acetate in hexane) toprovide the title compound. MS (DCI/NH₃) m/z 454 (M+H)⁺.

Example 464B6-(benzyloxymethyl)-8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)pyrido(3,2-d)pyridazin-5(6H)-one

The title compound was prepared according to procedure for EXAMPLE 101,substituting EXAMPLE 464A for EXAMPLE 103. MS (ESI) m/z 459 (M+H)⁺.

Example 464C8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one

A mixture of EXAMPLE 464B (130 mg, 0.28 mmol), 5% platinum on carbon (25mg), 5% Pd(OH)₂ on carbon (25 mg), concentrated aqueous HCl (66 μL) anddimethylformamide (10 ml) was stirred in a pressure vessel at roomtemperature under 40 psi of hydrogen for 48 hours. The volatiles wereremoved, the residue was separated by HPLC (Zorbax® C-18 ODS packingmaterial [Agilent Technologies, Santa Clara, Calif.], 0.1%TFA/CH₃CN/H₂O) to provide the title product as TFA salt. MS (ESI) m/z343 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.57-1.81 (m, 2H), 2.01-2.18(m, 2H), 2.26-2.46 (m, 4H), 3.17 (m, 2H), 3.72 (t, J=6.94 Hz, 2H), 3.84(s, 2H), 6.39 (s, 1H), 7.16-7.19 (m, 1H), 7.18-7.25 (m, 1H), 7.29 (dd,J=7.54, 1.98 Hz, 1H), 11.89 (s, 1H).

Example 465 methyl2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoate

The title compound was prepared as TFA salt according to procedure forEXAMPLE 414, substituting EXAMPLE 462A for EXAMPLE 369. MS (EST) m/z 318(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.61-1.75 (m, 2H), 2.34 (t, J=6.15Hz, 2H), 3.17 (m, 2H), 3.44 (s, 3H), 3.84 (s, 2H), 6.39 (s, 1H), 7.27(dd, J=10.91, 8.53 Hz, 1H), 7.46-7.56 (m, 1H), 7.76 (dd, J=7.14, 2.38Hz, 1H), 11.84 (s, 1H).

Example 4678-(3-amino-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one

The title compound was prepared as TFA salt according to procedure forEXAMPLE 414, substituting EXAMPLE 463 for EXAMPLE 369. MS (ESI) m/z 275(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 1.62-1.74 (m, 2H), 2.35 (t, J=6.27Hz, 2H), 3.10-3.23 (m, 2H), 3.69 (s, 2H), 4.91 (s, 2H), 6.25 (s, 1H),6.45-6.54 (m, 1H), 6.64 (dd, J=8.82, 2.03 Hz, 1H), 6.92 (dd, J=11.53,8.48 Hz, 1H), 11.93 (s, 1H).

Example 4682-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzoicacid

The title compound was prepared according to procedure for EXAMPLE 288,substituting EXAMPLE 465 for EXAMPLE 266. MS (EST) m/z 304 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 1.61-1.77 (m, 2H), 2.34 (t, J=6.10 Hz, 2H),3.06-3.25 (m, 2H), 3.84 (s, 2H), 6.36 (s, 1H), 7.22 (dd, J=10.85, 8.48Hz, 1H), 7.39-7.52 (m, 1H), 7.73 (dd, J=7.12, 2.37 Hz, 1H), 11.82 (s,1H) 13.19 (s, 1H).

Example 470N-ethyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and ethylamine for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 331 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): 1.09 (t, J=7.14 Hz, 3H), 1.58-1.74 (m, 2H),2.34 (t, J=6.15 Hz, 2H), 3.12-3.20 (m, 2H), 3.20-3.29 (m, 2H), 3.82 (s,2H), 6.39 (s, 1H), 7.19 (dd, J=10.31, 8.33 Hz, 1H), 7.30-7.38 (m, 1H),7.47 (dd, J=6.74, 2.38 Hz, 1H), 8.17-8.29 (m, 1H), 11.88 (s, 1H).

Example 471N-cyclobutyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, andcyclobutanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS(ESI) m/z 357 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.56-1.77 (m, 4H),1.90-2.10 (m, 2H), 2.12-2.28 (m, 2H), 2.33 (t, J=6.35 Hz, 2H), 3.05-3.25(m, 2H), 3.81 (s, 2H), 4.27-4.45 (m, 1H), 6.35 (s, 1H), 7.18 (dd,J=10.31, 8.33 Hz, 1H), 7.26-7.37 (m, 1H), 7.42 (dd, J=6.74, 2.38 Hz,1H), 8.49 (d, J=7.54 Hz, 1H), 11.84 (s, 1H).

Example 4722-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-pyrrolidin-1-ylethyl)benzamide

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and2-(pyrrolidin-1-yl)ethanamine for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 400 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.76 (m, 2H), 1.76-1.93 (m, 2H),1.93-2.10 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 2.61-2.76 (m, 2H), 2.96-3.12(m, 2H), 3.12-3.22 (m, 2H), 3.25-3.40 (m, 2H), 3.52-3.68 (m, 2H), 3.84(s, 2H), 6.35 (s, 1H), 7.25 (dd, J=10.85, 8.48 Hz, 1H), 7.33-7.49 (m,1H), 7.57 (dd, J=7.12, 2.37 Hz, 1H), 8.31-8.50 (m, 1H), 11.84 (s, 1H).

Example 4738-(4-fluoro-3-((4-(morpholin-4-ylcarbonyl)piperazin-1-yl)carbonyl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, andmorpholino(piperazin-1-yl)methanone for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (EST) m/z 485 (M+H)⁺;¹H NMR (300 MHz, DMSO-d): δ 1.60-1.78 (m, 2H), 2.35 (t, J=6.15 Hz, 2H),3.05-3.28 (m, 12H), 3.51-3.58 (m, 4H), 3.60-3.70 (m, 2H), 3.82 (s, 2H),6.41 (s, 1H), 7.16-7.29 (m, 2H), 7.29-7.37 (m, 1H), 11.92 (s, 1H).

Example 474N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-N′-phenylpentanediamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and5-oxo-5-(phenylamino)pentanoic acid for 1-methylcyclopropanecarboxylicacid. MS (ESI) m/z 464 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d): δ 1.62-1.75 (m,2H), 1.81-1.96 (m, 2H), 2.34 (t, J=7.12 Hz, 4H), 2.42 (t, J=8.14 Hz,2H), 3.09-3.22 (m, 2H), 3.77 (s, 2H), 6.30 (s, 1H), 6.93-7.07 (m, 1H),7.14 (dd, J=10.85, 8.48 Hz, 1H), 7.22-7.34 (m, 3H), 7.59 (d, J=7.80 Hz,2H), 7.68-7.77 (m, 1H), 9.62 (s, 1H), 9.87 (s, 1H), 11.82 (s, 1H).

Example 4751-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidine-2,5-dioneExample 475A4-(2-fluoro-5-((5-oxo-5,6-dihydropyrido(3,2-d)pyridazin-8-yl)methyl)phenylamino)-4-oxobutanoicacid

The title compound was prepared according to procedure for EXAMPLE 3,substituting EXAMPLE 463 for EXAMPLE 2. MS (ESI) m/z 371 (M+H)⁺.

Example 475B1-(2-fluoro-5-((5-oxo-5,6-dihydropyrido(3,2-d)pyridazin-8-yl)methyl)phenyl)pyrrolidine-2,5-dione

The title compound was prepared according to procedure for EXAMPLE 4,substituting EXAMPLE 475A for EXAMPLE 3. MS (ESI) m/z 353 (M+H)⁺.

Example 475C1-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidine-2,5-dione

The title compound was prepared according to procedure for EXAMPLE 414,substituting EXAMPLE 475B for EXAMPLE 369. MS (ESI) m/z 357 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ 1.58-1.78 (m, 2H), 2.33 (t, J=6.27 Hz, 2H),2.72-2.90 (m, 4H), 3.07-3.23 (m, 2H), 3.84 (s, 2H), 6.34 (s, 1H), 7.13(dd, J=6.95, 2.20 Hz, 1H), 7.27-7.37 (m, 1H), 7.37-7.43 (m, 1H), 11.83(s, 1H).

Example 476N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-methoxypropanamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and3-methoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS(ESI) m/z 361 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.74 (m, 2H),2.33 (t, J=6.15 Hz, 2H), 2.60 (t, J=6.15 Hz, 2H), 3.09-3.21 (m, 2H),3.24 (s, 3H), 3.59 (t, J=6.15 Hz, 2H), 3.77 (s, 2H), 6.33 (s, 1H),6.93-7.05 (m, 1H), 7.14 (dd, J=10.91, 8.53 Hz, 1H), 7.69-7.80 (m, 1H),9.63 (s, 1H), 11.85 (s, 1H).

Example 477N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-5-oxohexanamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and5-oxohexanoic acid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z387 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 1.64-1.80 (m, 4H), 2.08 (s, 3H),2.27-2.39 (m, 4H), 2.42-2.50 (m, 2H), 3.10-3.23 (m, 2H), 3.77 (s, 2H),6.34 (s, 1H), 6.94-7.04 (m, 1H), 7.13 (dd, J=10.85, 8.48 Hz, 1H),7.66-7.71 (m, 1H), 9.58 (s, 1H), 11.86 (s, 1H).

Example 478N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-phenoxypropanamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and3-phenoxypropanoic acid for 1-methylcyclopropanecarboxylic acid. MS(ESI) m/z 423 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.55-1.74 (m, 2H),2.33 (t, J=6.15 Hz, 2H), 2.84 (t, J=6.15 Hz, 2H), 3.08-3.21 (m, 2H),3.78 (s, 2H), 4.24 (t, J=6.15 Hz, 2H), 6.36 (s, 1H), 6.88-6.96 (m, 3H),6.97-7.05 (m, 1H), 7.16 (dd, J=10.91, 8.53 Hz, 1H), 7.25-7.31 (m, 2H),7.77 (dd, J=7.54, 1.98 Hz, 1H), 9.79 (s, 1H), 11.89 (s, 1H).

Example 479N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-4-oxo-4-phenylbutanamide

The title compound was prepared according to the procedure for EXAMPLE136, substituting EXAMPLE 467 for EXAMPLE 89, and 4-oxo-4-phenylbutanoicacid for 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 435 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.73 (m, 2H), 2.32 (t, J=5.95 Hz, 2H),2.75-2.79 (m, 2H), 3.08-3.19 (m, 2H), 3.27-3.36 (m, 2H), 3.75 (s, 2H),6.27 (s, 1H), 6.91-7.04 (m, 1H), 7.14 (dd, J=10.91, 8.53 Hz, 1H), 7.54(t, J=7.54 Hz, 2H), 7.59-7.69 (m, 1H), 7.70-7.77 (m, 1H), 7.94-8.03 (m,2H), 9.74 (s, 1H), 11.78 (s, 1H).

Example 4812-(4-(benzyloxy)phenoxy)-N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)acetamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and2-(4-(benzyloxy)phenoxy)acetic acid for 1-methylcyclopropanecarboxylicacid. MS (ESI) m/z 515 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 1.53-1.81(m, 2H), 2.22-2.39 (m, 2H), 3.07-3.21 (m, 2H), 3.78 (s, 2H), 4.66 (s,2H), 5.04 (s, 2H), 6.34 (s, 1H), 6.83-6.99 (m, 4H), 7.02-7.10 (m, 1H),7.14-7.23 (m, 1H), 7.30-7.37 (m, 2H), 7.37-7.46 (m, 3H), 7.65 (dd,J=7.54, 1.98 Hz, 1H), 9.77 (s, 1H), 11.84 (s, 1H).

Example 483N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)phenyl)-2-(4-methoxyphenoxy)acetamide

The title compound was prepared as TFA salt according to the procedurefor EXAMPLE 136, substituting EXAMPLE 467 for EXAMPLE 89, and2-(4-methoxyphenoxy)acetic acid for 1-methylcyclopropanecarboxylic acid.MS (ESI) m/z 438 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 1.63-1.75 (m, 2H),2.33 (t, J=6.27 Hz, 2H), 3.08-3.24 (m, 2H), 3.70 (s, 3H), 3.79 (s, 2H),4.66 (s, 2H), 6.35 (s, 1H), 6.84-6.96 (m, 4H), 7.01-7.11 (m, 1H), 7.18(dd, J=10.85, 8.48 Hz, 1H), 7.66 (dd, J=7.63, 2.20 Hz, 1H), 9.73 (s,1H), 11.85 (s, 1H).

Example 484N-cyclopropyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, andcyclopropanamine for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS(ESI) m/z 343 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 0.44-0.59 (m, 2H),0.63-0.76 (m, 2H), 1.60-1.78 (m, 2H), 2.34 (t, J=6.35 Hz, 2H), 2.74-2.90(m, 1H), 3.09-3.22 (m, 2H), 3.81 (s, 2H), 6.39 (s, 1H), 7.03-7.25 (m,1H), 7.25-7.37 (m, 1H), 7.42 (dd, J=6.74, 2.38 Hz, 1H), 8.33 (d, J=3.97Hz, 1H), 11.89 (s, 1H).

Example 4858-(3-((4-(2-ethoxyethyl)piperazin-1-yl)carbonyl)-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-one

The title compound was prepared as TFA salt according to procedure forEXAMPLE 48, substituting EXAMPLE 468 for EXAMPLE 48C, and1-(2-ethoxyethyl)piperazine for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 444 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): 1.09 (t, J=9.0 Hz, 3H), 1.61-1.76 (m, 2H),2.56-2.69 (m, 2H), 3.01-3.11 (m, 2H), 3.11-3.24 (m, 4H), 3.35-3.43 (m,4H), 3.43-3.61 (m, 4H), 3.82 (s, 2H), 6.35 (s, 1H), 7.18-7.26 (m, 1H),7.28-7.34 (m, 1H), 7.34-7.41 (m, 1H), 11.84 (s, 1H).

Example 4862-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(2,3-d)pyridazin-8-yl)methyl)-N-(2-piperidin-1-ylethyl)benzamide

The title compound was prepared according to procedure for EXAMPLE 48,substituting EXAMPLE 468 for EXAMPLE 48C, and2-(piperidin-1-yl)ethanamine for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 414 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): 1.33-1.49 (m, 2H), 1.50-1.64 (m, 4H),1.62-1.75 (m, 2H), 2.33 (t, J=6.35 Hz, 2H), 2.54-2.82 (m, 4H), 3.10-3.20(m, 2H), 3.20-3.35 (m, 2H), 3.37-3.55 (m, 2H), 3.82 (s, 2H), 6.35 (s,1H), 7.20 (dd, J=10.51, 8.53 Hz, 1H), 7.33-7.44 (m, 1H), 7.53 (dd,J=7.14, 2.38 Hz, 1H), 8.51 (dd, J=4.36, 1.59 Hz, 1H) 11.83 (s, 1H).

Example 4872-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido(3,2-d)pyridazin-8-yl)methyl)-N-(2-oxo-2-(piperidin-1-yl)ethyl)benzamide

The title compound was prepared according to procedure for EXAMPLE 48,substituting EXAMPLE 468 for EXAMPLE 48C, and2-amino-1-(piperidin-1-yl)ethanone for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 428 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): 1.44 (m, 2H), 1.48-1.65 (m, 4H), 1.65-1.79(m, 2H), 2.33 (t, J—=6.27 Hz, 2H), 3.10-3.24 (m, 2H), 3.34-3.42 (m, 2H),3.41-3.50 (m, 2H), 3.84 (s, 2H), 4.13 (d, J=5.09 Hz, 2H), 6.00-6.50 (m,1H), 7.05-7.28 (m, 1H), 7.32-7.53 (m, 1H), 7.63 (dd, J=7.12, 2.37 Hz,1H), 8.17 (q, J=5.09 Hz, 1H), 11.82 (s, 1H).

Example 4904-(4-fluoro-3-((4-pyrimidin-2-ylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 1 (100 mg, 0.33 mmol) in dimethlyacetamide (5mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) (126 mg, 0.33 mmol) andtriethylamine (92 μL, 0.66 mmol) and stirred for 20 minutes at roomtemperature. (Piperazin-1-yl)pyrimidine dihydrochloride (78 mg, 0.33mmol) was then added and the reaction mixture was stirred at roomtemperature for 16 hours. After concentration, the residual oil waspurified by HPLC (Zorbax®J C-18 ODS packing material [AgilentTechnologies, Santa Clara, Calif.], 0.1% TFA/CH₃CN/H₂O) to provide thetitle product. MS (DCI/NH₃) m/z 449 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.53-1.71 (m, 4H), 2.32-2.44 (m, 4H), 3.24-3.39 (m, 2H), 3.67-3.78 (m,4H), 3.79-3.88 (m, 2H), 3.93 (s, 2H), 6.67 (t, J=4.75 Hz, 1H), 7.21-7.23(m, 1H), 7.24-7.28 (m, 1H), 7.30-7.35 (m, 1H), 8.39 (d, J=4.75 Hz, 2H),12.62 (br s, 1H).

Example 4914-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared according to the procedure for EXAMPLE461, substituting 2-pyrrolidinone for 2-azetidinone in EXAMPLE 461B. MS(DCI/NH₃) m/z 328 (M+H)⁺; ¹H NMR (400 MHz, CD₂OD): δ 1.73-1.79 (m, 2H),1.83-1.90 (m, 2H), 2.22-2.29 (m, 2H), 2.55-2.60 (m, 4H), 2.69 (t, J=5.83Hz, 2H), 3.91 (t, J=7.06 Hz, 2H), 7.35-7.41 (m, 1H), 7.48-7.52 (m, 1H),7.60-7.64 (m, 1H).

Example 4924-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 492A 3-hydroxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g, 165.6mmol) in tetrahydrofuran (125 mL) placed in an ice bath was added sodiumborohydride (1.51 g, 39.97 mmol). The ice bath was removed and themixture was stirred at room temperature for 30 minutes, and under refluxfor 5 hours. After cooling to room temperature, 1N HCl was added, andthe reaction mixture concentrated. The residue was partitioned betweenethyl acetate and brine. The organic layer was washed with brine, waterand concentrated. The residue was purified by flash chromatography onsilica gel eluting with 50% ethyl acetate in hexanes to provide thetitle compound. MS (ESI) m/z 155 (M+H)⁺.

Example 492B

tributyl(3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl)phosphoniumbromide

To a flask charged with EXAMPLE 1A (3.0 g, 19.5 mmol) in acetic acid (10mL) was added tri-n-butyl phosphine (4.81 mL, 19.5 mmol) and a 33%solution of HBr in acetic acid (3.34 mL, 13.65 mmol). The reactionmixture was refluxed for 21 hours, and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 10% methanolin dichloromethane to provide the title compound. MS (DCI/NH₃) m/z 420(M+H)⁺.

Example 492C(E)-3-(3-bromo-4-fluorobenzylidene)-2,3,4,5,6,7-hexahydro-1H-inden-1-one

To a solution of EXAMPLE 492B (27.3 g, 65 mmol) in anhydrousdichloromethane (200 mL) was added 3-bromo-4-fluorobenzaldehyde (13.2 g,65 mmol) and triethylamine (9.0 mL, 65 mmol). The reaction mixture wasstirred at ambient temperature for 18 hours, and concentrated. Theresidue was partitioned between ethyl acetate and brine. The organicswere concentrated, and purified by flash chromatography on silica geleluting with 50% ethyl acetate in hexanes to provide the title compound.MS (DCI/NH₃) m/z 325 (M+H)⁺.

Example 492D4-(3-bromo-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of EXAMPLE 492C (16 g, 49.5 mmol) in ethanol (200 mL) wastreated with hydrazine monohydrate (4.8 mL, 99 mmol) at 80° C. for 2hours, and cooled to room temperature. The mixture was filtered and thesolid was dried to provide the title compound. MS (DCI/NH₃) m/z 339(M+H)⁺.

Example 492E methyl2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoate

A 250 mL pressure bottle was charged with EXAMPLE 492D (7.3 g, 21.65mmol), a mixture of methanol (60 mL) and N,N-dimethylformamide (5 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.317 g,0.433 mmol), and triethylamine (6.04 ml, 43.3 mmol). The mixture waspurged, and pressurized with carbon monoxide (60 psi), and stirred at110° C. for 16 hours. Solid material was filtered off, and the filtratewas concentrated. The residue was purified by flash chromatography onsilica gel eluting with 50% ethyl acetate in hexanes to provide thetitle compound. MS (DCI/NH₃) m/z 317 (M+H)⁺.

Example 492F2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)benzoicacid

A solution of EXAMPLE 492E (5.7 g, 18 mmol) in 1:1 tetrahydrofuran/water(100 mL) was treated with lithium hydroxide monohydrate (1.5 g, 36 mmol)at ambient temperature for 16 hours. The reaction mixture was acidifiedwith 2 N HCl to a pH 3, and concentrated. The residue was partitionedbetween ethyl acetate and brine. The organics were concentrated anddried to provide the title compound. MS (DCI/NH₃) m/z 303 (M+H)⁺.

Example 492G4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 492F (390 mg, 1.3 mmol) in dimethylacetamide(10 mL) was added 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU) and triethylamine (0.36mL, 2.6 mmol). The reaction mixture was stirred at ambient temperaturefor 16 hours and concentrated. The residue was partitioned between ethylacetate and brine. The organics were concentrated, and the residue waspurified by HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) to provide the titlecompound as the TFA salt. The TFA salt was dissolved in a mixture ofmethylene chloride and methanol, and treated with 1M HCl in ether.Concentration of the mixture yielded the title compound as the HCl salt.MS (DCI/NH₃) m/z 439 (M+H)⁺; ¹H NMR (CD₃OD) δ 0.79-0.93 (m, 4H),1.70-1.76 (m, 4H), 1.86-2.05 (m, 1H), 2.46-2.57 (m, 4H), 3.33-3.45 (m,2H), 3.52-3.64 (m, 2H), 3.65-3.78 (m, 2H), 3.80-3.93 (m, 2H), 4.03 (s,2H), 7.17 (t, J=8.92 Hz, 1H), 7.24-7.29 (m, 1H), 7.33-7.40 (m, 1H).

Example 493 methyl4-({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)-4-oxobutanoateExample 493A 3-(benzyloxycarbonylamino)-4-fluorobenzoic acid

To a solution of 3-amino-4-fluorobenzoic acid (30 g, 193 mmol) in amixture of tetrahydrofuran (300 mL) and water (300 mL) was added cesiumcarbonate (157 g, 483 mmol) and benzyl chloroformate (30.4 mL, 213mmol). This mixture was stirred at ambient temperature for 16 hours, andwas concentrated to about 200 mL. The residue was acidified with 2N HClto a pH 3, and was partitioned between ethyl acetate and brine. Theprecipitated solid was collected by filtration, washed with ethylacetate and water, and dried to provide the title compound. MS (DCI/NH₃)m/z 290 (M+H)⁺.

Example 493B benzyl 2-fluoro-5-(methoxy(methyl)carbamoyl)phenylcarbamate

To a solution of EXAMPLE 493A (38.4 g, 133 mmol) in a mixture of dioxane(500 mL) and dichloromethane (200 mL) was addedN,O-dimethylhydroxylamine hydrochloride (29.2 g, 299 mmol) andtriethylamine. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC) (57.3 g, 299 mmol) and N-hydroxybenzotriazole (HOBt)(40.4 g, 299 mmol) were added. The reaction mixture stirred at roomtemperature for 16 hours and concentrated. The crude mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, and concentrated. The residue was purified by flashchromatography eluting with 40% ethyl acetate in hexanes to provide thetitle compound. MS (DCI/NH₃) m/z 333 (M+H)⁺.

Example 493C

To a solution of EXAMPLE 493B (27 g, 81 mmol) in anhydroustetrahydrofuran (100 mL) was added lithium aluminum hydride solution(1M) in tetrahydrofuran (41 mL) at 0° C. After stirring at 0° C. for 15minutes, the reaction was quenched with water. The mixture waspartitioned between ethyl acetate and dilute aqueous HCl solution. Theorganics were washed with water and concentrated. The residue waspurified by flash chromatography eluting with 25% ethyl acetate inhexanes to provide the title compound. MS (DCI/NH₃) m/z 274 (M+H)⁺.

Example 493D (Z)-benzyl2-fluoro-5-((3-oxo-4,5,6,7-tetrahydroisobenzofuran-1(3H)-ylidene)methyl)phenylcarbamate

To a solution of EXAMPLE 492B (25.2 g, 60.2 mmol) in dichloromethane(200 mL) was added EXAMPLE 493C (16.5 g, 60.2 mmol) and triethylamine(8.3 mL, 60.2 mmol). The reaction mixture was stirred at ambienttemperature for 16 hours and concentrated. Ethyl acetate was added andthe mixture washed with water and brine. The organics were concentratedand dried to provide the title compound. MS (DCI/NH₃) m/z 394 (M+H)⁺.

Example 493E benzyl2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylcarbamate

To a solution of EXAMPLE 493D (14.6 g, 37.1 mmol) in ethanol (150 mL)was added hydrazine monohydrate (3.6 mL, 74.2 mmol) and the mixture washeated at 80° C. for 16 hours. The mixture was cooled and theprecipitated solid was filtered and dried to provide the title compound.MS (DCI/NH₃) m/z 408 (M+H)⁺.

Example 493F4-(3-amino-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 493E (1.65 g, 4.05 mmol) in tetrahydrofuran(100 mL) was added 20% Pd(OH)₂/C (0.32 g) under nitrogen. The suspensionwas purged, and pressurized with hydrogen at 30 psi with stirring for 1hour. The solid material was filtered off and the filtrate concentratedto provide the title compound. MS (DCI/NH₃) m/z 274 (M+H)⁺.

Example 493G4-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenylamino)-4-oxobutanoicacid

To a solution of EXAMPLE 493F (1.1 g, 4 mmol) in a mixture ofacetonitrile (20 mL) and dioxane (20 mL) was added succinic anhydride(800 mg, 8 mmol). The mixture was stirred at 80° C. for 18 hours, andconcentrated. The crude solid was triturated from methanol to providethe title compound. MS (DCI/NH₃) m/z 374 (M+H)⁺.

Example 493H methyl4-({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)-4-oxobutanoate

To a solution of EXAMPLE 493G (230 mg, 0.6 mmol) inN,N-dimethylformamide (8 mL) was added potassium bicarbonate (123 mg,1.23 mmol) and iodomethane (0.08 mL, 1.23 mmol). The mixture was stirredat room temperature for 16 hours and was concentrated. The residue waspurified by flash chromatography on silica gel eluting with 8% methanolin dichloromethane to provide the title compound. MS (DCI/NH₃) m/z 388(M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.52-1.69 (m, 4H), 2.27-2.43 (m, 4H),2.53-2.61 (m, 2H), 2.61-2.68 (m, 2H), 3.59 (s, 3H), 3.85 (s, 2H),6.89-6.96 (m, 1H), 7.15 (dd, J=11.10, 8.33 Hz, 1H), 7.72 (d, J=7.54 Hz,1H), 9.72 (s, 1H), 12.61 (s, 1H).

Example 4944-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-N,N-dimethylpiperazine-1-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z442 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.76 (m, 4H), 2.41-2.48 (m, 2H),2.48-2.55 (m, 2H), 2.86 (s, 6H), 3.17-3.23 (m, 2H), 3.32-3.40 (m, 4H),3.75-3.82 (m, 2H), 3.99 (s, 2H), 7.12-7.18 (m, 1H), 7.23 (dd, J=6.29,2.30 Hz, 1H), 7.32-7.37 (m, 1H).

Example 4954-(4-fluoro-3-{[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z482 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.52-1.59 (m, 4H), 1.60-1.67 (m, 2H),1.69-1.77 (m, 4H), 2.41-2.47 (m, 2H), 2.48-2.54 (m, 2H), 3.18-3.22 (m,2H), 3.23-3.28 (m, 4H), 3.33-3.40 (m, 4H), 3.75-3.80 (m, 2H), 3.99 (s,2H), 7.15 (t, J=8.90 Hz, 1H), 7.23 (dd, J=6.44, 2.15 Hz, 1H), 7.32-7.37(m, 1H).

Example 4964-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z449 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.69-1.78 (m, 4H), 2.42-2.48 (m, 2H),2.49-2.57 (m, 2H), 3.44-3.51 (m, 2H), 3.61-3.69 (m, 2H), 3.74-3.80 (m,2H), 3.87-3.92 (m, 2H), 4.00 (s, 2H), 7.13-7.21 (m, 1H), 7.26 (dd,J=6.29, 2.30 Hz, 1H), 7.34-7.39 (m, 1H), 7.83 (d, J=2.46 Hz, 1H), 8.16(dd, J=2.61, 1.38 Hz, 1H), 8.25 (s, 1H).

Example 4974-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z448 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.77 (m, 4H), 2.42-2.49 (m, 2H),2.49-2.55 (m, 2H), 3.55-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.86-3.92 (m,2H), 3.92-3.97 (m, 2H), 4.01 (s, 2H), 7.14-7.18 (m, 2H), 7.18-7.22 (m,1H), 7.29 (dd, J=6.44, 2.46 Hz, 1H), 7.36-7.43 (m, 1H), 8.17 (d, J=7.67Hz, 2H).

Example 4981-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-4-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z413 (M+H)⁺.

Example 4994-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base? according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z463 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.68-1.77 (m, 4H), 2.38 (s, 3H), 2.43-2.49(m, 2H), 2.49-2.56 (m, 2H), 3.43-3.51 (m, 2H), 3.58-3.66 (m, 2H),3.73-3.78 (m, 2H), 3.88 (dd, J=6.44, 3.99 Hz, 2H), 4.00 (s, 2H),7.14-7.21 (m, 1H), 7.26 (dd, J=6.44, 2.15 Hz, 1H), 7.34-7.40 (m, 1H),7.73 (s, 1H), 8.02 (s, 1H).

Example 5001-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z413 (M+H)⁺.

Example 5014-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z442 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.69-1.76 (m, 4H), 2.42-2.47 (m, 2H),2.48-2.53 (m, 2H), 2.56-2.62 (m, 2H), 2.68-2.75 (m, 2H), 2.84 (t, J=6.14Hz, 2H), 2.93 (s, 6H), 3.31-3.36 (m, 2H), 3.38-3.45 (m, 2H), 3.79-3.88(m, 2H), 3.99 (s, 2H), 7.13-7.19 (m, 1H), 7.21 (dd, J=6.29, 2.30 Hz,1H), 7.33-7.39 (m, 1H).

Example 5024-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z399 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.77 (m, 4H), 2.11-2.33 (m, 2H),2.41-2.48 (m, 2H), 2.49-2.56 (m, 2H), 2.90-2.95 (m, 1H), 2.98 (s, 3H),3.34-3.43 (m, 1H), 3.44-3.58 (m, 3H), 3.61-3.70 (m, 1H), 3.71-3.78 (m,1H), 3.82-3.91 (m, 1H), 4.00 (s, 2H), 7.15-7.20 (m, 1H), 7.26-7.30 (m,1H), 7.36-7.41 (m, 1H).

Example 5034-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z386 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.39-1.49 (m, 1H), 1.50-1.59 (m, 1H),1.69-1.74 (m, 4H), 1.77-1.85 (m, 1H), 1.90-1.98 (m, 1H), 2.41-2.47 (m,2H), 2.48-2.55 (m, 2H), 3.12-3.23 (m, 1H), 3.33-3.41 (m, 1H), 3.45-3.55(m, 1H), 3.83-3.93 (m, 1H), 3.99 (s, 2H), 4.13-4.22 (m, 1H), 7.11-7.17(m, 1H), 7.18-7.22 (m, 1H), 7.30-7.36 (m, 1H).

Example 504N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z387 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.69-1.76 (m, 4H), 2.42-2.47 (m, 2H),2.48-2.54 (m, 2H), 2.99 (s, 3H), 3.01 (s, 6H), 3.45 (t, J=6.26 Hz, 2H),3.91 (t, J=6.26 Hz, 2H), 4.00 (s, 2H), 7.15-7.20 (m, 1H), 7.28 (dd,J=6.41, 2.44 Hz, 1H), 7.37-7.41 (m, 1H).

Example 505N,N-diethyl-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperidine-3-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z469 (M+H)⁺.

Example 5068-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneExample 506A (3-bromo-4-fluorobenzyl)magnesium bromide

To a mixture of magnesium turnings (1.36 g, 56 mmol) and2-bromo-4-(bromomethyl)-1-fluorobenzene (5.0 g, 18.6 mmol) in diethylether (100 mL) was added a granule of iodine. The slightly purplesuspension was stirred at ambient temperature for 5-10 minutes, and thecolor of the mixture disappeared. The exothermic mixture was refluxedwith stirring for an additional 1 hour, and cooled to room temperature.The formed Grignard reagent was directly used in the next step withoutfurther purification.

Example 506B methyl 2-(2-(3-bromo-4-fluorophenyl)acetyl)nicotinate

To a solution of dimethylpyridine-2,3-dicarboxylate (5.45 g, 19 mmol) intetrahydrofuran (200 mL) was added a suspension of 506A (19 mmol) at−78° C. The mixture was stirred at −78° C. for 30 minutes, and warmed toroom temperature and quenched with water. This mixture was partitionedbetween ethyl acetate and brine. The organic phase was washed with brineand concentrated. The residue was purified by flash chromatography (15%ethyl acetate in hexane) to give the title compound. MS (DCI/NH₃) m/z353 (M+H)⁺.

Example 506C 8-(3-bromo-4-fluorobenzyl)pyrido[3,2-d]pyridazin-5(6H)-one

A solution of EXAMPLE 506B (3.2 g, 9.1 mmol) in ethanol (50 mL) wastreated with hydrazine (455 mg, 9.1 mmol) at 90° C. for 5 hours. Solidprecipitated, and after cooling to room temperature, was collected byfiltration, washed with ethanol, and dried to give the title compound.MS (DCI/NH₃) m/z 335 (M+H)⁺.

Example 506D methyl2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)benzoate

A 250 mL high pressure vessel was charged with EXAMPLE 506C (4.5 g,13.47 mmol), methanol (50 mL), N,N-dimethylformamide (50 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.099 g,0.135 mmol) and triethylamine (3.75 ml, 26.9 mmol). The mixture waspurged and pressurized with carbon monoxide (60 psi), and stirred at100° C. for 5 hours. Solid material was filtered off and the filtratewas concentrated. The solid was collected by filtration, washed withmethanol, and dried to give the title compound. MS (DCI/NH₃) m/z 314(M+H)⁺.

Example 506E methyl2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazin-8-yl)methyl)benzoate

In a 250 mL high pressure vessel, EXAMPLE 506D (3.3 g, 10.53 mmol) and5% Pt/C (0.330 g, 1.692 mmol) were suspended in 30 mL of acetic acid.This suspension was purged and pressurized with 30 psi of hydrogen, andstirred at ambient temperature for 32 hours.

Solid material was filtered off and the filtrate concentrated. Theformed solid was collected by filtration, washed with methanol and driedto give the title compound. MS (DCI/NH₃) m/z 318 (M+H)⁺.

Example 506F2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazin-8-yl)methyl)benzoicacid

A solution of EXAMPLE 506E (2.8 g, 8.8 mmol) in tetrahydrofuran (150 mL)was treated with LiOH (253 mg, 10.6 mmol) in water (20 mL) at 50° C.overnight. After cooling to room temperature, the mixture was acidifiedwith dilute HCl to pH 4, and concentrated to about 10 mL. The solidmaterial was collected by filtration, washed with water and dried toprovide the title compound. MS (DCI/NH₃) m/z 305 (M+H)⁺.

Example 506G8-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

To a solution of EXAMPLE 506F (100 mg, 0.33 mmol) in anhydrousN,N-dimethylformamide (2 mL) was addedcyclopropyl(piperazin-1-yl)methanone (66 mg, 0.43 mmol),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (82mg, 0.43 mmol), N-hydroxybenzotriazole (HOBT) (66 mg, 0.43 mmol) andtriethyl amine (44 mg, 0.43 mmol). The reaction mixture was warmed untilhomogeneous. The solution was stirred at ambient temperature for 16hours and concentrated. The residue was purified by HPLC (Zorbax C-18,0.1% TFA/CH₃CN/H₂O) to provide the title compound as the TFA salt. MS(DCI/NH₃) m/z 440 (M+H); ¹H NMR (DMSO-d₆) δ 0.60-0.82 (m, 4H), 1.59-1.79(m, 2H), 1.94 (m, 1H), 2.34 (t, J=6.27 Hz, 2H), 3.00-3.35 (m, 4H),3.38-3.79 (m, 2H), 3.82 (s, 2H), 3.83-4.11 (m, 4H), 6.37 (s, 1H),7.15-7.27 (m, 1H), 7.24-7.30 (m, 1H), 7.30-7.40 (m, 1H), 11.87 (s, 1H).

Example 5071-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}piperidine-2,6-dioneExample 507A2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)benzamide

EXAMPLE 506D (1.5 g, 4.8 mmol) was suspended in a solution of NH₃ inmethanol (7N, 50 mL) in a pressure tube. The tube was sealed and heatedat 110° C. for 48 hours. After cooling to room temperature theprecipitate was collected by filtration, washed with methanol, and driedto give the title compound. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 507B 8-(3-amino-4-fluorobenzyl)pyrido[3,2-d]pyridazin-5(6H)-one

To a mixture of ice (30 g) and solution of KOH (1.7 g, 30.2 mmol) inwater (2 mL) was added bromine (0.17 ml, 3.35 mmol) at −10° C. Afterstirring at −10° C. for 10 minutes, EXAMPLE 507A (1.0 g, 3.35 mmol) wasadded. The mixture was stirred at −10° C. for an additional 10 minutesand at 65° C. for 1 hour. After cooling, the mixture was acidified withHCl to pH 7, and partitioned between brine and ethyl acetate. Theorganic phase was washed with brine, and concentrated. The residue waspurified by flash chromatography (70% ethyl acetate in hexane) to givethe title compound. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 507C1-(2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)phenyl)piperidine-2,6-dione

To a solution of EXAMPLE 507B (200 mg, 0.74 mmol) in acetonitrile (20mL) was added dihydro-2H-pyran-2,6(3H)-dione (84 mg, 0.74 mmol). Themixture was stirred at 80° C. for 6 days and concentrated. The residuewas dissolved in dichloromethane (20 mL) and treated with1,1′-carbonyldiimidazole (CDI) (104 mg, 0.74 mmol) at ambienttemperature for 5 days. The mixture was concentrated and the residuepartitioned between ethyl acetate and brine. The organic phase waswashed with brine, and was concentrated. The residue was purified byflash chromatography (2%-15% gradient methanol in ethyl acetate) toprovide the title compound. MS (DCI/NH₃) m/z 367 (M+H)⁺.

Example 507D1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}piperidine-2,6-dione

To a solution of EXAMPLE 507C (200 mg, 0.546 mmol) inN,N-dimethylformamide (20 mL) in a 100 mL pressure bottle was added 5%Pt/C (60.0 mg, 0.308 mmol) and concentrated HCl (55 μl, 1.2 eq). Thereaction mixture was purged and pressurized with hydrogen (30 psi), andstirred at ambient temperature for 3 days. An additional 60 mg of 5%Pt/C and 40 μL of concentrated HCl were added and the mixture stirred atambient temperature for 3 days. Solid material was filtered off and thefiltrate was concentrated. The residue was purified by HPLC (ZorbaxC-18, 0.1% TFA/CH₃CN/H₂O) to provide the title compound as the TFA salt.MS (DCI/NH₃) m/z 371 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.58-1.78 (m, 2H),1.82-2.10 (m, 2H), 2.34 (t, J=6.15 Hz, 2H), 2.76 (t, J=6.35 Hz, 4H),3.81 (s, 2H), 3.79-4.01 (m, 2H), 6.37 (s, 1H), 7.07 (dd, J=7.14, 2.38Hz, 1H), 7.18-7.28 (m, 1H), 7.28-7.38 (m, 1H), 11.88 (s, 1H).

Example 5088-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z371 (M+H)⁺.

Example 5098-{4-fluoro-3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z400 (M+H)⁺

Example 5108-{4-fluoro-3-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z449 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.60-1.82 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.09-3.25 (m, 2H), 3.43 (m, 2H), 3.68 (m, 2H), 3.74-3.88 (m, 4H),3.84 (s, 2H), 6.38 (s, 1H), 7.17 (d, J=7.12 Hz, 2H), 7.21-7.29 (m, 1H),7.28-7.33 (m, 1H), 7.34-7.42 (m, 1H), 8.30 (d, J=7.46 Hz, 2H), 11.86 (s,1H).

Example 5118-{4-fluoro-3-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z450 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.61-1.76 (m, 2H), 2.34 (t, J=6.15 Hz,2H), 3.10-3.24 (m, 2H), 3.34 (m, 2H), 3.54 (m, 2H), 3.67 (m, 2H), 3.74(m, 2H), 3.83 (s, 2H), 6.43 (s, 1H), 7.20-7.27 (m, 1H), 7.28 (dd,J=6.54, 2.18 Hz, 1H), 7.31-7.38 (m, 1H), 7.87 (d, J=2.78 Hz, 1H), 8.10(d, J=2.78 Hz, 1H), 8.32 (s, 1H), 11.95 (s, 1H).

Example 5124-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-N,N-dimethylpiperazine-1-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z443 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.37-1.52 (m, 2H), 2.09 (t, J=6.15 Hz,2H), 2.17-2.29 (m, 2H), 2.75-2.85 (m, 2H), 2.91 (m, 6H), 2.91-3.01 (m,4H), 3.38 (m, 2H), 3.56 (s, 2H), 6.17 (s, 1H), 6.91-6.99 (m, 1H),6.97-7.03 (m, 1H), 7.04-7.10 (m, 1H), 11.68 (s, 1H).

Example 513N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z388 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.57-1.77 (m, 2H), 2.33 (t, J=6.15 Hz,2H), 2.74-2.97 (m, 1H), 2.85 (s, 3H), 2.86 (s, 3H), 2.87 (s, 3H), 3.16(m, 2H), 3.24-3.40 (m, 1H), 3.74-3.82 (m, 2H), 3.82 (s, 2H), 6.36 (s,1H), 7.17-7.30 (m, 2H), 7.32-7.44 (m, 1H), 11.85 (s, 1H).

Example 5144-(3-{[4-(3-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z495 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.73 (m, 4H), 2.33-2.44 (m, 4H),3.03-3.24 (m, 2H), 3.35-3.55 (m, 2H), 3.64-3.90 (m, 6H), 4.29 (s, 2H),7.21-7.24 (m, 1H), 7.24-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.41-7.46 (m,1H), 7.47-7.52 (m, 1H), 7.52-7.55 (m, 1H), 7.59 (s, 1H), 12.61 (br s,1H).

Example 5154-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z447 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.69 (m, 4H), 2.31-2.43 (m, 4H),3.03-3.13 (m, 2H), 3.18-3.27 (m, 2H), 3.31-3.40 (m, 2H), 3.73-3.82 (m,2H), 3.92 (s, 2H), 6.82 (t, J=7.21 Hz, 1H), 6.92-6.95 (m, 1H), 6.95-6.98(m, 1H), 7.20-7.25 (m, 3H), 7.26 (d, J=6.14 Hz, 1H), 7.28-7.33 (m, 1H),12.60 (br s, 1H).

Example 5168-{4-fluoro-3-[(4-methylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z386 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.52-1.78 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 2.84 (s, 3H), 2.92-3.25 (m, 6H), 3.39 (m, 2H), 3.57 (m, 2H), 3.83(s, 2H), 6.37 (s, 1H), 7.06-7.36 (m, 2H), 7.33-7.51 (m, 1H), 11.86 (s,1H).

Example 5174-(3-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z481 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.70 (m, 4H), 2.33-2.43 (m, 4H),2.87-2.96 (m, 2H), 2.99-3.06 (m, 2H), 3.33-3.42 (m, 2H), 3.76-3.85 (m,2H), 3.93 (s, 2H), 7.04-7.10 (m, 1H), 7.16 (dd, J=7.98, 1.53 Hz, 1H),7.23 (d, J=2.76 Hz, 1H), 7.24-7.27 (m, 1H), 7.28-7.30 (m, 1H), 7.30-7.34(m, 1H), 7.43 (dd, J=7.98, 1.53 Hz, 1H), 12.61 (br s, 1H).

Example 5184-(3-{[4-(2-chlorobenzyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z495 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.54-1.70 (m, 4H), 2.32-2.43 (m, 4H),3.08-3.29 (m, 2H), 3.36-3.52 (m, 2H), 3.96-4.20 (m, 6H), 4.32 (s, 2H),7.23-7.29 (m, 2H), 7.31-7.37 (m, 1H), 7.43-7.50 (m, 2H), 7.55-7.60 (m,1H), 7.63-7.68 (m, 1H), 12.61 (br s, 1H).

Example 5191-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-3-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z414 (M+H)⁺.

Example 5204-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z413 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-1.68 (m, 4H), 2.00 (s, 1.5H), 2.02(s, 1.5H), 2.32-2.41 (m, 4H), 3.14-3.21 (m, 1H), 3.21-3.27 (m, 1H),3.35-3.43 (m, 2H), 3.48-3.55 (m, 2H), 3.55-3.62 (m, 1H), 3.63-3.70 (m,1H), 3.92 (s, 2H), 7.20-7.27 (m, 2H), 7.28-7.32 (m, 1H), 12.63 (br s,1H).

Example 5224-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z465 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.70 (m, 4H), 2.31-2.43 (m, 4H),3.28-3.37 (m, 2H), 3.56-3.66 (m, 2H), 3.69-3.80 (m, 4H), 3.92 (s, 2H),6.63 (dd, J=3.38, 1.84 Hz, 1H), 7.02 (d, J=3.38 Hz, 1H), 7.21-7.27 (m,2H), 7.28-7.35 (m, 1H), 7.84 (s, 1H), 12.61 (br s, 1H)

Example 5234-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z465 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-1.69 (m, 4H), 2.31-2.44 (m, 4H),2.90-2.98 (m, 2H), 3.02-3.10 (m, 2H), 3.32-3.38 (m, 2H), 3.75-3.83 (m,2H), 3.93 (s, 2H), 6.97-7.02 (m, 1H), 7.02-7.08 (m, 1H), 7.08-7.13 (m,1H), 7.14-7.18 (m, 1H), 7.20-7.23 (m, 1H), 7.23-7.27 (m, 1H), 7.28-7.33(m, 1H), 12.61 (br s, 1H).

Example 5244-(3-{[4-(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z483 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-1.71 (m, 4H), 2.32-2.43 (m, 4H),2.86-2.94 (m, 2H), 2.97-3.06 (m, 2H), 3.31-3.42 (m, 2H), 3.74-3.83 (m,2H), 3.92 (s, 2H), 6.96-7.03 (m, 1H), 7.05-7.13 (m, 1H), 7.17-7.21 (m,1H), 7.22-7.23 (m, 1H), 7.24-7.27 (m, 1H), 7.28-7.33 (m, 1H), 12.61 (brs, 1H).

Example 5254-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z475 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.54-1.69 (m, 4H), 2.31-2.44 (m, 4H),3.21-3.35 (m, 2H), 3.39-3.52 (m, 2H), 3.52-3.63 (m, 2H), 3.66-3.78 (m,2H), 3.91 (s, 2H), 7.19-7.26 (m, 2H), 7.27-7.33 (m, 1H), 7.39-7.49 (m,5H), 12.60 (br s, 1H).

Example 5268-(4-fluoro-3-{[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z483 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.36-1.58 (m, 6H), 1.62-1.79 (m, 2H),2.34 (t, J=0.10 Hz, 2H), 2.98-3.10 (m, 2H), 3.10-3.27 (m, 10H), 3.64 (m,2H), 3.82 (s, 2H), 6.37 (s, 1H), 7.17-7.24 (m, 1H), 7.23-7.28 (m, 1H),7.28-7.37 (m, 1H), 11.88 (s, 1H).

Example 5274-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z465 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.57-1.70 (m, 4H), 2.32-2.45 (m, 4H),3.09-3.16 (m, 2H), 3.23-3.29 (m, 2H), 3.30-3.37 (m, 2H), 3.71-3.79 (m,2H), 3.92 (s, 2H), 6.55-6.61 (m, 1H), 6.72-6.76 (m, 1H), 6.76-6.79 (m,1H), 7.19-7.25 (m, 2H), 7.25-7.28 (m, 1H), 7.28-7.34 (m, 1H), 12.60 (brs, 1H).

Example 5284-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z465 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.70 (m, 4H), 2.31-2.44 (m, 4H),2.97-3.06 (m, 2H), 3.10-3.20 (m, 2H), 3.29-3.38 (m, 2H), 3.72-3.83 (m,2H), 3.92 (s, 2H), 6.95-7.00 (m, 2H), 7.04-7.10 (m, 2H), 7.20-7.24 (m,1H), 7.23-7.28 (m, 1H), 7.28-7.34 (m, 1H), 12.61 (br s, 1H).

Example 5294-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z448 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.70 (m, 4H), 2.31-2.44 (m, 4H),3.33-3.43 (m, 2H), 3.52-3.59 (m, 2H), 3.64-3.73 (m, 2H), 3.74-3.82 (m,2H), 3.93 (s, 2H), 6.80-6.86 (m, 1H), 7.09 (d, J=8.59 Hz, 1H), 7.22-7.29(m, 2H), 7.30-7.37 (m, 1H), 7.76-7.84 (m, 1H), 8.10 (dd, J=5.52, 1.84Hz, 1H), 12.61 (br s, 1H).

Example 530N,N-diethyl-4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z470 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=7.06 Hz, 6H), 1.57-1.67 (m,4H), 2.32-2.42 (m, 4H), 2.99-3.06 (m, 2H), 3.10-3.17 (m, 6H), 3.19-3.26(m, 2H), 3.57-3.66 (m, 2H), 3.91 (s, 2H), 7.19-7.22 (m, 1H), 7.22-7.25(m, 1H), 7.26-7.32 (m, 1H), 12.60 (br s, 1H).

Example 5314-{4-fluoro-3-[(4-isopropylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z413 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.26 (d, J=6.75 Hz, 6H), 1.54-1.69 (m,4H), 2.32-2.43 (m, 4H), 2.87-3.01 (m, 1H), 3.05-3.23 (m, 2H), 3.29-3.45(m, 2H), 3.48-3.63 (m, 3H), 3.93 (s, 2H), 4.64 (d, J=6.44 Hz, 1H),7.23-7.30 (m, 2H), 7.32-7.38 (m, 1H), 12.62 (br s, 1H).

Example 5328-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z483 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.60-1.75 (m, 2H), 1.77-1.86 (m, 2H),1.89-1.94 (m, 2H), 2.34 (t, J=6.10 Hz, 2H), 3.08-3.25 (m, 4H), 3.26-3.45(m, 6H), 3.56 (m, 4H), 3.83 (s, 2H), 4.21 (s, 2H), 6.36 (s, 1H),7.13-7.33 (m, 2H), 7.32-7.51 (m, 1H), 11.85 (s, 1H).

Example 5334-(4-fluoro-3-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z484 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-1.67 (m, 4H), 2.30-2.41 (m, 4H),3.11 (dd, J=6.14, 3.38 Hz, 2H), 3.13-3.17 (m, 4H), 3.19-3.25 (m, 4H),3.53-3.57 (m, 4H), 3.59-3.66 (m, 2H), 3.91 (s, 2H), 7.19-7.22 (m, 1H),7.22-7.25 (m, 1H), 7.27-7.32 (m, 1H), 12.60 (br s, 1H).

Example 5341-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidine-4-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z414 (M+H)⁺.

Example 5358-(4-fluoro-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z416 (M+H)⁺.

Example 5368-{4-fluoro-3-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z450 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.39-1.85 (m, 2H), 2.33 (t, J=6.10 Hz,2H), 3.06-3.21 (m, 2H), 3.24-3.35 (m, 2H), 3.55-3.96 (m, 8H), 6.40 (s,1H), 6.67 (t, J=4.75 Hz, 1H), 7.16-7.26 (m, 1H), 7.24-7.30 (m, 1H),7.30-7.39 (m, 1H), 8.38 (d, J=4.75 Hz, 2H), 11.91 (s, 1H).

Example 5374-(4-fluoro-3-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 492. MS (DCI/NH₃) m/z482 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.69-1.76 (m, 4H), 1.93 (q, J=6.55 Hz, 2H),2.01 (q, J=6.55 Hz, 2H), 2.42-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.34-3.41(m, 2H), 3.43 (t, J=6.75 Hz, 4H), 3.49 (t, J=6.90 Hz, 4H), 3.67-3.77 (m,2H), 4.00 (s, 2H), 4.19 (s, 2H), 7.19 (dd, J=9.51, 8.59 Hz, 1H), 7.29(dd, J=6.29, 2.30 Hz, 1H), 7.38-7.43 (m, 1H).

Example 538N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-isopropylurea

To a solution of EXAMPLE 493F (75 mg, 0.27 mmol) inN,N-dimethylformamide (8 mL) was added isopropyl isocyanate (23 mg, 0.27mmol) and triethylamine (0.12 mL, 0.81 mmol). The reaction mixture wasstirred at 70° C. for 16 hours and was concentrated. The residue waspurified by HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) to provide the titlecompound. MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 539N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N′-propylurea

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 538. MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 540N-cyclopentyl-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 538. MS (DCI/NH₃) m/z 385 (M+H)⁺.

Example 541N-(2,4-difluorophenyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 538. MS (DCI/NH₃) m/z 429 (M+H)⁺.

Example 542N-(tert-butyl)-N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}urea

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 538. MS (DCI/NH₃) m/z 373 (M+H)⁺.

Example 543 benzyl4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carboxylate

To a solution of EXAMPLE 492F (1.5 g, 5 mmol) in N,N-dimethylformamide(20 mL) was added benzylpiperazine-1-carboxylate (1.09 g, 5 mmol),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (1.9g, 10 mmol), N-hydroxybenzotriazole (HOBt) (1.34 g, 10 mmol), andtriethylamine (1.4 mL, 10 mmol). The reaction mixture was stirred atambient temperature for 16 hours and was concentrated. The residue wasdiluted with ethyl acetate and washed with brine. The organic layer wasconcentrated and the residue purified by flash chromatography on silicagel eluting with 60% ethyl acetate in hexanes to provide the titlecompound. MS (DCI/NH₃) m/z 505 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.77 (m,4H), 2.39-2.56 (m, 4H), 3.33-3.37 (m, 2H), 3.42-3.54 (m, 2H), 3.54-3.65(m, 2H), 3.71-3.80 (m, 2H), 3.98 (s, 2H), 5.14 (s, 2H), 7.11-7.19 (m,1H), 7.23 (dd, J=6.35, 2.38 Hz, 1H), 7.29-7.32 (m, 1H), 7.33-7.38 (m,5H).

Example 544 benzyl4-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate

The title compound was prepared, using the appropriate reagents, as afree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 519 (M+H)⁺.

Example 5458-{4-fluoro-3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as TFAsalt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z 449(M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.60-1.80 (m, 2H), 2.35 (t, J=6.10 Hz, 2H),3.10-3.24 (m, 2H), 3.39 (m, 2H), 3.55 (m, 2H), 3.68 (m, 2H), 3.73-3.81(m, 2H), 3.84 (s, 2H), 6.41 (s, 1H), 6.78-6.88 (m, 1H), 7.09 (d, J=8.81Hz, 1H), 7.20-7.28 (m, 1H), 7.26-7.32 (m, 1H), 7.32-7.42 (m, 1H), 7.79(t, J=7.29 Hz, 1H), 8.00-8.14 (m, 1H), 11.90 (s, 1H).

Example 5468-{4-fluoro-3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z448 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.52-1.78 (m, 2H), 2.34 (t, J=6.10 Hz,2H), 3.09 (m, 2H), 3.13-3.26 (m, 4H), 3.35 (m, 2H), 3.68-3.85 (m, 2H),3.83 (s, 2H), 6.36 (s, 1H), 6.82 (t, J=7.29 Hz, 1H), 6.96 (d, J=7.80 Hz,2H), 7.22 (d, J=8.48 Hz, 2H), 7.24-7.30 (m, 2H), 7.30-7.39 (m, 1H),11.85 (s, 1H).

Example 5478-(4-fluoro-3-{[4-(3-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z466 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.87 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.07-3.22 (m, 4H), 3.21-3.30 (m, 2H), 3.34 (m, 2H), 3.76 (m, 2H),3.83 (s, 2H), 6.41 (s, 1H), 6.49-6.70 (m, 1H), 6.69-6.86 (m, 2H),7.12-7.25 (m, 1H), 7.22-7.31 (m, 2H), 7.31-7.45 (m, 1H), 11.91 (s, 1H).

Example 5488-(4-fluoro-3-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z466 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.53-1.86 (m, 2H), 2.35 (t, J=6.15 Hz,2H), 3.03 (m, 2H), 3.09-3.24 (m, 4H), 3.36 (m, 2H), 3.78 (m, 2H), 3.83(s, 2H), 6.43 (s, 1H), 6.94-7.02 (m, 2H), 7.02-7.12 (m, 2H), 7.19-7.31(m, 2H), 7.30-7.40 (m, 1H), 11.94 (s, 1H).

Example 5498-(4-fluoro-3-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z466 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.61-1.81 (m, 2H), 2.34 (t, J=6.15 Hz,2H), 2.96 (m, 2H), 3.00-3.12 (m, 2H), 3.13-3.22 (m, 2H), 3.38 (m, 2H),3.80 (m, 2H), 3.83 (s, 2H), 6.38 (s, 1H), 6.96-7.05 (m, 1H), 7.06-7.13(m, 2H), 7.13-7.19 (m, 1H), 7.19-7.30 (m, 2H), 7.30-7.38 (m, 1H), 11.87(s, 1H).

Example 5508-(3-{[4-(2,4-difluorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z 466 (M+H)⁺;¹H NMR (DMSO-d₆) δ 1.62-1.77 (m, 2H), 2.34 (t, J=6.35 Hz, 2H), 2.90 (m,2H), 2.96-3.06 (m, 2H), 3.17 (m, 2H), 3.29-3.48 (m, 2H), 3.79 (m, 2H),3.82 (s, 2H), 6.35 (s, 1H), 7.02 (dd, J=7.93, 2.78 Hz, 1H), 7.08 (dd,J=9.12, 5.95 Hz, 1H), 7.16-7.22 (m, 1H), 7.22-7.30 (m, 2H), 7.30-7.38(m, 1H), 11.85 (s, 1H).

Example 551 8-{3-[(4-benzoylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z476 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.57-1.78 (m, 2H), 2.34 (t, J=6.10 Hz,2H), 3.17 (m, 4H), 3.21-3.37 (m, 2H), 3.45 (m, 2H), 3.69 (m, 2H), 3.82(s, 2H), 6.40 (s, 1H), 7.18-7.30 (m, 2H), 7.29-7.38 (m, 1H), 7.39-7.50(m, 5H), 11.92 (s, 1H).

Example 5538-(4-fluoro-3-{[4-(2-furoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z466 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.59-1.79 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.06-3.25 (m, 2H), 3.33 (m, 2H), 3.65 (m, 2H), 3.68-3.81 (m, 4H),3.83 (s, 2H), 6.43 (s, 1H), 6.63 (dd, J=3.56, 1.86 Hz, 1H), 7.03 (dd,J=3.39, 0.68 Hz, 1H), 7.18-7.31 (m, 2H), 7.31-7.39 (m, 1H), 7.83-7.86(m, 1H), 11.93 (s, 1H).

Example 5548-(3-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, (as aTFA salt?) according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z482 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-1.80 (m, 2H), 2.34 (t, J=6.27 Hz,2H), 2.75-2.98 (m, 2H), 2.96-3.09 (m, 2H), 3.17 (m, 2H), 3.35 (m, 2H),3.74-3.83 (m, 2H), 3.83 (s, 2H), 6.36 (s, 1H), 7.02-7.10 (m, 1H), 7.17(dd, J=8.14, 1.36 Hz, 1H), 7.20-7.31 (m, 2H), 7.30-7.38 (m, 2H), 7.43(dd, J=7.97, 1.53 Hz, 1H), 11.85 (s, 1H).

Example 5554-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-2-morpholin-4-ylpiperazine-1-carbaldehyde

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z482 (M+H)¹.

Example 5568-(4-fluoro-3-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z450 (M+H); ¹H NMR (DMSO-d₆) δ 1.63-1.81 (m, 2H), 2.35 (t, J=6.27 Hz,2H), 2.91 (m, 3H), 3.09 (m, 2H), 3.12-3.24 (m, 4H), 3.32 (m, 2H), 3.74(m, 2H), 3.82 (s, 2H), 6.38 (s, 1H), 7.17-7.29 (m, 2H), 7.31-7.39 (m,1H), 11.89 (s, 1H).

Example 557N,N-diethyl-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z471 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=6.95 Hz, 6H), 1.51-1.85 (m,2H), 2.35 (t, J=6.27 Hz, 2H), 3.04 (m, 2H), 3.07-3.38 (m, 10H), 3.64 (m,2H), 3.82 (s, 2H), 6.39 (s, 1H), 7.02-7.28 (m, 2H), 7.26-7.45 (m, 1H),11.90 (s, 1H).

Example 5598-{3-[(4-acetylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z412 (M+H)⁺.

Example 5602-(4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazin-1-yl)-N,N-dimethylacetamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z457 (M+H)⁺.

Example 5618-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z492 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.61-1.84 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.17 (m, 6H), 3.58 (s, 4H), 3.83 (s, 2H), 4.19-4.53 (m, 4H), 6.37(s, 1H), 6.94-7.06 (m, 3H), 7.21-7.45 (m, 5H), 11.86 (s, 1H).

Example 5628-(4-fluoro-3-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z512 (M+H)⁺; ¹H NMR (DMSO-d₆) 1.54-1.73 (m, 2H), 2.34 (t, J=6.10 Hz, 2H),2.88 (m, 2H), 2.92-3.03 (m, 2H), 3.07-3.18 (m, 2H), 3.30 (m, 2H),3.66-3.77 (m, 2H), 3.83 (s, 2H), 6.32 (s, 1H), 6.94-7.23 (m, 2H),7.22-7.44 (m, 1H), 7.44-7.87 (m, 5H), 11.84 (s, 1H).

Example 5632-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z429 (M+H)⁺.

Example 5648-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z440 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.29-1.86 (m, 8H), 2.01 (m, 2H), 2.35 (t,J=6.10 Hz, 2H), 2.98 (m, 1H), 3.03-3.29 (m, 4H), 3.43 (m, 2H), 3.56 (m,4H), 3.83 (s, 2H), 6.38 (s, 1H), 7.04-7.34 (m, 2H), 7.34-7.54 (m, 1H),11.86 (s, 1H).

Example 5658-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z442 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 0.99 (d, J=4.41 Hz, 6H), 1.61-1.78 (m,2H), 2.35 (t, J=6.10 Hz, 2H), 2.88 (m, 1H), 3.07-3.32 (m, 4H), 3.45 (m,2H), 3.58 (m, 4H), 3.82 (s, 2H), 6.40 (s, 1H), 7.04-7.31 (m, 2H),7.29-7.50 (m, 1H), 11.90 (s, 1H).

Example 5668-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z485 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.61-1.78 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 2.73 (m, 2H), 2.81-2.92 (m, 2H), 2.99 (m, 2H), 3.17 (m, 6H), 3.25(t, J=5.93 Hz, 2H), 3.35 (m, 2H), 3.73-3.82 (m, 6H), 3.83 (s, 2H), 6.39(s, 1H), 7.09-7.32 (m, 2H), 7.29-7.54 (m, 1H), 11.88 (s, 1H).

Example 5678-(4-fluoro-3-{[4-(pyrrolidine-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z468 (M+H)⁺.

Example 5688-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z482 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.04-1.42 (m, 5H), 1.47-1.81 (m, 6H),2.35 (t, J=6.10 Hz, 2H), 3.08-3.29 (m, 6H), 3.43 (s, 2H), 3.57 (s, 4H),3.82 (s, 2H), 6.39 (s, 1H), 7.09-7.31 (m, 2H), 7.28-7.46 (m, 1H), 11.90(s, 1H).

Example 5698-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z470 (M+H)⁺.

Example 5708-(4-fluoro-3-{[4-(2-piperidin-1-ylethyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z483 (M+H)⁺; ¹H NMR (DMSO-d₆) 1.53 (m, 2H), 1.72 (m, 6H), 2.34 (t, J=6.27Hz, 2H), 2.64 (m, 2H), 2.69-2.85 (m, 2H), 2.92 (m, 2H), 3.11-3.23 (m,4H), 3.23-3.41 (m, 4H), 3.59-3.78 (m, 2H), 3.83 (s, 2H), 6.38 (s, 1H),6.99-7.31 (m, 2H), 7.28-7.52 (m, 1H), 11.86 (s, 1H).

Example 5714-(4-fluoro-3-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 484 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.68-1.77 (m, 4H),2.41-2.47 (m, 2H), 2.49-2.55 (m, 2H), 2.60-2.70 (m, 2H), 2.74-2.82 (m,2H), 2.92 (t, J=5.95 Hz, 2H), 3.32-3.36 (m, 6H), 3.40-3.48 (m, 2H),3.82-3.87 (m, 2H), 3.89-3.95 (m, 4H), 3.99 (s, 2H), 7.14-7.19 (m, 1H),7.21 (dd, J=6.41, 2.14 Hz, 1H), 7.35-7.39 (m, 1H).

Example 5728-{4-fluoro-3-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z387 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.15-1.44 (m, 2H), 1.56-1.86 (m, 4H),2.34 (t, J=6.10 Hz, 2H), 2.94-3.11 (m, 1H), 3.11-3.24 (m, 3H), 3.25-3.41(m, 1H), 3.61-3.79 (m, 1H), 3.82 (s, 2H), 3.92-4.14 (m, 1H), 6.40 (s,1H), 6.89-7.25 (m, 2H), 7.24-7.45 (m, 1H), 11.90 (s, 1H).

Example 5738-(4-fluoro-3-{[4-(6-methylpyrazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z464 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.64-1.78 (m, 2H), 2.31 (s, 3H), 2.35 (t,J=6.27 Hz, 2H), 3.11-3.26 (m, 2H), 3.35 (m, 2H), 3.52 (m, 2H), 3.67 (m,2H), 3.74 (m, 2H), 3.84 (s, 2H), 6.44 (s, 1H), 7.20-7.31 (m, 2H),7.31-7.39 (m, 1H), 7.78 (s, 1H), 8.12 (s, 1H), 11.95 (s, 1H).

Example 5744-(4-fluoro-3-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 511 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.64-1.75 (m, 4H),2.37-2.44 (m, 2H), 2.45-2.54 (m, 2H), 2.94-3.01 (m, 2H), 3.04-3.16 (m,2H), 3.39-3.46 (m, 2H), 3.83 (t, J=5.03 Hz, 2H), 3.95 (s, 2H), 7.08-7.13(m, 1H), 7.15 (dd, J=6.41, 2.14 Hz, 1H), 7.30-7.35 (m, 1H), 7.63 (t,J=7.63 Hz, 2H), 7.71 (t, J=7.32 Hz, 1H), 7.77 (d, J=1.53 Hz, 1H), 7.79(s, 1H).

Example 5754-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 439 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.65-1.80 (m, 8H),1.80-1.90 (m, 2H), 2.10-2.25 (m, 2H), 2.41-2.47 (m, 2H), 2.49-2.56 (m,2H), 3.03-3.24 (m, 3H), 3.48-3.64 (m, 4H), 3.70-3.86 (m, 2H), 4.00 (s,2H), 7.17-7.21 (m, 1H), 7.30 (dd, J=6.41, 2.14 Hz, 1H), 7.39-7.42 (m,1H).

Example 5764-(4-fluoro-3-{[4-(pyrrolidine-1-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 468 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.69-1.77 (m, 4H),1.82-1.89 (m, 4H), 2.42-2.47 (m, 2H), 2.48-2.55 (m, 2H), 3.23-3.27 (m,2H), 3.34-3.39 (m, 8H), 3.39-3.44 (m, 1H), 3.76-3.81 (m, 2H), 3.99 (s,2H), 7.13-7.19 (m, 1H), 7.24 (dd, J=6.26, 2.29 Hz, 1H), 7.32-7.37 (m,1H).

Example 5774-(4-fluoro-3-{[4-(2-phenoxyethyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 491 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.66-1.79 (m, 4H),2.39-2.47 (m, 2H), 2.48-2.55 (m, 2H), 3.35-3.48 (m, 2H), 3.48-3.61 (m,4H), 3.64-3.69 (m, 2H), 3.69-3.78 (m, 2H), 4.00 (s, 2H), 4.34-4.44 (m,2H), 6.99-7.00 (m, 1H), 7.01-7.03 (m, 2H), 7.17-7.23 (m, 1H), 7.28-7.31(m, 1H), 7.30-7.35 (m, 2H), 7.38-7.44 (m, 1H).

Example 5782-fluoro-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 428 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.66-1.78 (m, 4H),2.38-2.46 (m, 2H), 2.46-2.56 (m, 2H), 2.81-2.87 (m, 3H), 2.89 (s, 3H),2.94-3.07 (m, 3H), 3.33-3.44 (m, 4H), 3.58 (t, J=6.26 Hz, 2H), 4.00 (s,2H), 7.16 (dd, J=10.83, 8.39 Hz, 1H), 7.38-7.42 (m, 1H), 7.59 (dd,J=6.87, 2.29 Hz, 1H).

Example 5794-{4-fluoro-3-[(4-isobutyrylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 441 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.04-1.17 (m, 6H),1.67-1.79 (m, 4H), 2.41-2.48 (m, 2H), 2.49-2.57 (m, 2H), 2.85-3.03 (m,1H), 3.32-3.45 (m, 2H), 3.54-3.63 (m, 2H), 3.66-3.73 (m, 2H), 3.73-3.86(m, 2H), 3.99 (s, 2H), 7.14-7.20 (m, 1H), 7.22-7.29 (m, 1H), 7.34-7.38(m, 1H).

Example 5804-{3-[(4-ethylpiperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/H₃) m/z 399 (M+H); ¹H NMR (CD₃OD) δ 1.37 (t, J=7.32 Hz, 3H),1.67-1.81 (m, 4H), 2.41-2.48 (m, 2H), 2.48-2.57 (m, 2H), 2.98-3.22 (m,2H), 3.26 (q, J=7.32 Hz, 2H), 3.40-3.87 (m, 6H), 4.00 (s, 2H), 7.17-7.22(m, 1H), 7.29 (dd, J=6.41, 2.14 Hz, 1H), 7.38-7.44 (m, 1H).

Example 581 benzyl(3S)-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-2,5-dioxopyrrolidin-3-ylcarbamate

To a solution of EXAMPLE 493F (200 mg, 0.732 mmol) in a mixture ofdioxane (6 mL) and acetonitrile (2 mL) was addedN-(carbobenzyloxy-L-aspartic anhydride (365 mg, 1.464 mmol). The mixturewas heated at 80° C. for 24 hours, cooled to ambient temperature andconcentrated. The residue was dissolved in anhydrous methylene chloride(10 mL) and was treated with 1,1′-carbonyldiimidazole (CDI) (356 mg,2.195 mmol) at ambient temperature overnight. The mixture was directlypurified by flash chromatography [0-15% methanol in 2:1 ethylacetate/hexane] to give a mixture of two major products. The slowerdiluting fraction was further purified by HPLC (Zorbax, C-18, 250×2.54column, Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN; 0-100%gradient) to provide the title compound as the TFA salt. MS (DCI/NH₃)m/z 399 (M+H)⁺.

Example 5823-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-isopropylimidazolidine-2,4-dioneExample 582A2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)benzamide

A solution of EXAMPLE 506D (1 g, 3.2 mmol) in methanol (20 mL) wastreated with 7N ammonia in methanol (15 mL) in a pressure tube at 90° C.overnight. After cooling to room temperature, the white solid materialwas collected by filtration, washed with methanol, and dried to give thetitle compound. MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 582B 8-(3-amino-4-fluorobenzyl)pyrido[3,2-d]pyridazin-5(6H)-one

To a mixture of ice (50 g) and a solution of KOH (2 g, 36 mmol) in 8 mLof water was added bromine (0.2 mL, 4 mmol) at −10° C. The mixture wasstirred at −10° C. for 10 minutes, and EXAMPLE 582A (1.2 g, 0.4 mmol)was added. This mixture was stirred at −10° C. for an additional 10minutes and at 65° C. for 1 hour. After cooling to room temperature, themixture was partitioned between water (100 mL) and ethyl acetate (200mL). The organic phase was washed with brine, water and concentrated toabout 10 mL. The formed solid material was washed with methanol anddried to give the title compound. MS (DCI/NH₃) m/z 271 (M+H)⁺.

Example 582C8-(3-amino-4-fluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyridazin-5(6H)-one

A mixture of EXAMPLE 582B (1.3 g, 4.8 mmol), 5% Pt/C (650 mg),concentrated HCl (0.8 mL) and N,N-dimethylformamide (150 mL) in apressure vessel was purged and pressurized with hydrogen at ambienttemperature for 16 hours. Solid material was filtered off and thefiltrate concentrated. The residue was purified by HPLC (Zorbax C-18,0.1% TFA/CH₃CN/H₂O) to provide the title compound as the TFA salt. MS(ESI) m/z 275 (M+H)⁺.

Example 582D3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-isopropylimidazolidine-2,4-dione

A suspension of EXAMPLE 582C (50 mg, 0.18 mmol) in CH₃CN (15 mL) washeated until homogeneous. After cooling, methyl2-isocyanato-3-methylbutanoate (32 mg, 0.18 mmol) was added, and themixture stirred at 65° C. overnight. The mixture was concentrated andthe residue dissolved in N,N-dimethylformamide (10 mL), 2N NaOH (1 mL)was added, and the mixture stirred at room temperature overnight.Solvent was removed and the residue purified by HPLC (Zorbax C-8, 0.1%TFA/CH₃CN/H₂O) to provide the title compound as the TFA salt. MS(DCI/NH₃) m/z 416 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 0.88 (d, J=6.74 Hz, 3H),0.92 (d, J=6.74 Hz, 3H), 1.56-1.75 (m, 2H), 1.98-2.19 (m, 1H), 2.34 (t,J=6.15 Hz, 2H), 3.01-3.27 (m, 2H), 3.74 (s, 2H), 4.10 (dd, J=8.53, 4.56Hz, 1H), 6.34 (s, 1H), 6.67-6.86 (m, 1H), 6.93 (d, J=8.72 Hz, 1H), 7.08(dd, J=11.50, 8.33 Hz, 1H), 8.48 (d, J=2.78 Hz, 1H), 11.90 (s, 1H).

Example 583(3S)-3-amino-1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}pyrrolidine-2,5-dione

To a solution of EXAMPLE 581 (150 mg, 0.297 mmol) in methanol (10 mL)was added 10% palladium on carbon (30 mg) under nitrogen. Thissuspension was purged with hydrogen, and stirred under hydrogen(balloon) for 1.5 hours. Solid material was filtered off and thefiltrate concentrated. The residue was purified by HPLC (Zorbax, C-18,250×2.54 column, Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN;0-100% gradient) to provide the title compound as the TFA salt. MS(DCI/NH₃) m/z 371 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.62 (m, 4H), 2.33-2.40 (m,4H), 2.84-2.93 (m, 1H), 3.18-3.30 (m, 1H), 3.96 (s, 2H), 4.56-4.65 (m,1H), 7.09 (d, J=5.83 Hz, 1H), 7.36-7.44 (m, 2H), 8.71 (s, 2H) 12.64 (s,1H).

Example 584N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-4-methylpiperazine-1-carboxamide

To a solution of EXAMPLE 493F (75 mg, 0.27 mmol) in 1:1tetrahydrofuran/acetonitrile (6 mL) was added4-methylpiperazine-1-carbonylchloride (179 mg, 1.1 mmol) andtriethylamine (56 mg, 0.55 mmol). The mixture was heated at 70° C. for18 hours and was concentrated. The residue was purified by HPLC (ZorbaxC-18, 0.1% TFA/CH₃CN/H₂O) to provide the title compound as a free base.MS (DCI/NH₃) m/z 400 (M+H)⁺.

Example 5854-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 427 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.06-1.15 (m, 3H),1.67-1.75 (m, 4H), 2.40 (q, J=7.63 Hz, 2H), 2.43-2.48 (m, 2H), 2.48-2.55(m, 2H), 3.32-3.43 (m, 2H), 3.51-3.59 (m, 2H), 3.62-3.71 (m, 2H),3.73-3.83 (m, 2H), 3.99 (s, 2H), 7.14-7.19 (m, 1H), 7.23-7.28 (m, 1H),7.33-7.38 (m, 1H).

Example 5864-(3-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18. 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 463 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.21 (t, J=7.48 Hz, 3H),1.55-1.72 (m, 4H), 2.32-2.43 (m, 4H), 3.08 (q, J=7.53 Hz, 2H), 3.11-3.18(m, 2H), 3.23-3.32 (m, 4H), 3.64-3.79 (m, 2H), 3.92 (s, 2H), 7.20-7.23(m, 1H), 7.23-7.27 (m, 1H), 7.29-7.33 (m, 1H), 12.63 (br s, 1H).

Example 5874-(3-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 455 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.28 (s, 9H), 1.68-1.77(m, 4H), 2.42-2.48 (m, 2H), 2.48-2.55 (m, 2H), 3.34-3.39 (m, 2H),3.60-3.67 (m, 2H), 3.73-3.81 (m, 4H), 4.00 (s, 2H), 7.14-7.19 (m, 1H),7.25 (dd, J=6.26, 2.29 Hz, 1H), 7.33-7.38 (m, 1H).

Example 5904-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 505 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.76 (m, 4H),2.42-2.48 (m, 2H), 2.47-2.53 (m, 2H), 3.33-3.45 (m, 2H), 3.54-3.62 (m,2H), 3.66-3.73 (m, 2H), 3.74-3.86 (m, 2H), 3.99 (s, 2H), 4.79 (s, 2H),6.92-7.00 (m, 3H), 7.16 (t, J=9.00 Hz, 1H), 7.23-7.30 (m, 3H), 7.33-7.39(m, 1H).

Example 5918-(4-fluoro-3-{[4-(phenoxyacetyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as TFAsalt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z 506(M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.58-1.78 (m, 2H), 2.34 (t, J=6.27 Hz, 2H),3.06-3.34 (m, 4H), 3.44 (m, 2H), 3.56 (m, 2H), 3.66 (m, 2H), 3.83 (s,2H), 4.84 (d, J=16.95 Hz, 2H), 6.39 (s, 1H), 6.84-6.99 (m, 3H),7.16-7.31 (m, 4H), 7.31-7.39 (m, 1H), 11.90 (s, 1H).

Example 5938-(3-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z456 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.19 (s, 9H), 1.50-1.80 (m, 2H), 2.35 (t,J=6.10 Hz, 2H), 2.97-3.32 (m, 4H), 3.47-3.58 (m, 2H), 3.62 (s, 4H), 3.83(s, 2H), 6.42 (s, 1H) 7.10-7.28 (m, 2H), 7.29-7.46 (m, 1H) 11.93 (s,1H).

Example 5948-(3-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z464 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.21 (t, J=7.46 Hz, 3H), 1.63-1.77 (m,2H), 2.35 (t, J=6.10 Hz, 2H), 3.08 (q, J=7.23 Hz, 2H), 3.13-3.22 (m,4H), 3.21-3.35 (m, 4H), 3.71 (s, 2H), 3.82 (s, 2H), 6.40 (s, 1H),7.08-7.28 (m, 2H), 7.29-7.47 (m, 1H), 11.91 (s, 1H).

Example 595N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidine-3-yl)-N-methylacetamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z428 (M+H)⁺.

Example 596N-ethyl-N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}pyrrolidine-3-yl)acetamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z442 (M+H)⁺.

Example 5978-{4-fluoro-3-[(4-propionylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z428 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 0.99 (t, J=6.95 Hz, 3H), 1.58-1.82 (m,2H), 2.22-2.44 (m, 4H), 3.04-3.31 (m, 4H), 3.41 (m, 2H), 3.52 (m, 2H),3.56-3.72 (m, 2H), 3.83 (s, 2H), 6.45 (s, 1H), 7.05-7.28 (m, 2H),7.28-7.50 (m, 1H), 11.96 (s, 1H).

Example 5983-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-methylimidazolidine-2,4-dione

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH₃) m/z372 (M+H)⁺.

Example 5998-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z478 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.62-1.79 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.02 (m, 2H), 3.07-3.24 (m, 4H), 3.39 (m, 2H), 3.70 (s, 3H), 3.81(m, 2H), 3.84 (s, 2H), 6.46 (s, 1H), 6.89 (d, J=8.48 Hz, 2H), 7.00 (d,J=8.81 Hz, 2H), 7.18-7.31 (m, 2H), 7.31-7.40 (m, 1H), 11.99 (s, 1H).

Example 6008-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z542 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.77 (m, 2H), 2.34 (t, J=6.10 Hz,2H), 2.74-2.89 (m, 2H), 2.94 (m, 2H), 3.09-3.19 (m, 2H), 3.24-3.36 (m,2H), 3.71 (m, 2H), 3.78 (s, 2H), 3.87 (s, 3H), 6.34 (s, 1H), 7.17 (d,J=8.81 Hz, 2H), 7.16-7.23 (m, 2H), 7.23-7.37 (m, 1H), 7.67 (d, J=9.15Hz, 2H), 11.87 (s, 1H).

Example 6018-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z506 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.57-1.80 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.09-3.22 (m, 2H), 3.29 (m, 2H), 3.48 (m, 2H), 3.55 (m, 2H), 3.69(m, 2H), 3.79 (s, 3H), 3.83 (s, 2H), 6.43 (s, 1H), 6.98 (d, J=8.48 Hz,2H), 7.16-7.30 (m, 2H), 7.28-7.36 (m, 1H), 7.40 (d, J=8.81 Hz, 2H),11.94 (s, 1H).

Example 6028-[4-fluoro-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z516 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.55-1.83 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.09-3.26 (m, 4H), 3.27-3.43 (m, 4H), 3.79 (m, 2H), 3.83 (s, 2H),6.41 (s, 1H), 7.11 (d, J=7.80 Hz, 1H), 7.17-7.32 (m, 4H), 7.31-7.39 (m,1H), 7.44 (t, J=7.80 Hz, 1H), 11.91 (s, 1H).

Example 603 tert-butyl3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}tetrahydropyrimidine-1(2H)-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m z542 (M+H)⁺; ¹H NMR (DMSO-d₆) 1.41 (s, 9H), 1.59 (m, 2H), 1.63-1.78 (m,2H), 2.33 (t, J=5.43 Hz, 2H), 3.14-3.22 (m, 2H), 3.21-3.38 (m, 1H),3.43-3.54 (m, 2H), 3.62-3.78 (m, 1H), 3.71-3.83 (m, 2H), 5.11 (s, 2H),6.38 (d, J=2.03 Hz, 1H), 7.00-7.29 (m, 2H), 7.29-7.59 (m, 1H), 11.89 (s,1H).

Example 6048-(3-{[3-[3-(dimethylamino)propyl]tetrahydropyrimidin-1(2H)-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z457 (M+H)⁺.

Example 6055-benzyl-3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}imidazolidine-2,4-dione

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH₃) m/z448 (M+H)⁺.

Example 6063-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 582. MS (DCI/NH₃) m/z372 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.68 (m, 2H), 2.27-2.37 (m, 2H), 2.40 (t,J=6.27 Hz, 2H), 3.17 (m, 2H), 3.33 (m, 2H), 3.73 (s, 2H), 6.24 (s, 1H),6.66-6.82 (m, 2H), 7.05 (dd, J=11.36, 8.31 Hz, 1H), 8.31 (s, 1H), 11.79(s, 1H).

Example 6078-{4-fluoro-3-[(3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z386 (M+H)⁺; ¹H NMR (DMSO-d₆) 1.47-1.78 (m, 2H), 2.34 (t, J=6.10 Hz, 2H),3.07-3.24 (m, 2H), 3.39 (m, 2H), 3.69-3.81 (m, 2H), 3.83 (s, 2H), 4.11(s, 2H), 6.38 (s, 1H), 7.04-7.30 (m, 2H), 7.31-7.41 (m, 1H), 8.13 (s,1H), 11.89 (s, 1H).

Example 6098-{3-[(4-benzoylpiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z475 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.38-1.58 (m, 2H), 1.59-1.74 (m, 2H),1.70-1.81 (m, 1H), 1.91 (m, 1H), 2.33 (t, 0.1=6.10 Hz, 2H), 2.90-3.08(m, 1H), 3.13-3.21 (m, 2H), 3.21-3.29 (m, 1H), 3.45 (m, 1H), 3.65-3.83(m, 1H), 3.82 (s, 2H), 4.52 (m, 1H), 6.39 (s, 1H), 7.14-7.28 (m, 2H),7.28-7.35 (m, 1H), 7.55 (t, J=7.29 Hz, 2H), 7.60-7.70 (m, 1H), 7.95-8.04(m, 2H), 11.88 (s, 1H).

Example 6108-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z505 (M+H)⁺; ¹H NMR (DMSO-d₆) 1.38-1.58 (m, 2H), 1.60-1.74 (m, 3H),1.81-1.88 (m, 1H), 2.33 (t, J=6.10 Hz, 2H), 2.91-3.06 (m, 1H), 3.17 (m,2H), 3.19-3.30 (m, 1H), 3.45 (m, 1H), 3.72 (m, 1H), 3.82 (s, 2H), 3.85(s, 3H), 4.52 (m, 1H), 6.41 (s, 1H), 7.06 (d, J=9.15 Hz, 2H), 7.13-7.26(m, 2H), 7.27-7.36 (m, 1H), 7.99 (d, J=9.15 Hz, 2H), 11.89 (s, 1H).

Example 6118-(4-fluoro-3-{[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z515 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.60-1.74 (m, 2H), 2.34 (t, J=6.10 Hz,2H), 3.17 (m, 2H), 3.30 (m, 2H), 3.52 (m, 2H), 3.57-3.66 (m, 2H), 3.69(m, 2H), 3.82 (s, 2H), 6.48 (s, 1H), 7.06 (m, 2H), 7.16-7.30 (m, 2H),7.30-7.38 (m, 1H), 7.47 (dd, J=4.92, 2.20 Hz, 2H), 7.58 (d, J=8.14 Hz,1H), 11.30 (s, 1H), 11.91 (s, 1H).

Example 6128-(3-{[4-(3-chlorobenzoyl)piperidin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z510 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.36-1.55 (m, 2H), 1.61-1.74 (m, 3H),1.81-1.88 (m, 1H), 2.33 (t, J=6.10 Hz, 2H), 2.91-3.09 (m, 1H), 3.12-3.20(m, 2H), 3.20-3.32 (m, 1H), 3.44 (m, 1H), 3.69-3.81 (m, 1H), 3.82 (s,2H), 4.51 (m, 1H), 6.41 (s, 1H), 7.13-7.27 (m, 2H), 7.26-7.36 (m, 1H),7.58 (t, J=7.80 Hz, 1H), 7.73 (dd, J=7.46, 1.70 Hz, 1H), 7.90-8.04 (m,2H), 11.90 (s, 1H).

Example 613 benzyl4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z 506 (M+H)⁺;¹H NMR (DMSO-d₆) δ 1.51-1.76 (m, 2H), 2.33 (t, J=6.10 Hz, 2H), 3.17 (m,2H), 3.24 (m, 2H), 3.35-3.44 (m, 2H), 3.48 (m, 2H), 3.64 (m, 2H), 3.81(s, 2H), 5.10 (s, 2H), 6.34 (s, 1H), 7.17-7.28 (m, 2H), 7.29-7.36 (m,1H), 7.34-7.40 (m, 5H), 11.83 (s, 1H).

Example 614 tert-butyl(3R)-4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-3-phenylpiperazine-1-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z548 (M+H)⁺.

Example 6168-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z490 (M+H)⁺.

Example 6178-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as TFAsalt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z 372(M+H)⁺.

Example 618

N′-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methyl-N-phenylurea

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 584. MS (DCI/NH₃) m/z407 (M+H)⁺.

Example 619N-ethyl-N-(1-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}pyrrolidine-3-yl)acetamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 441 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 0.89-1.15 (m, 3H),1.52-1.65 (m, 4H), 1.90-2.00 (m, 2H), 2.01-2.16 (m, 3H), 2.27-2.40 (m,4H), 3.18-3.32 (m, 4H), 3.35-3.43 (m, 2H), 3.60-3.74 (m, 1H), 3.90 (s,2H), 7.17-7.25 (m, 2H), 7.25-7.32 (m, 1H), 12.60 (br s, 1H).

Example 6204-[4-fluoro-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 541 (M+H)⁺.

Example 6214-[4-fluoro-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 515 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.68-1.77(m, 4H), 2.43-2.48 (m, 2H), 2.49-2.55 (m, 2H), 3.16-3.24 (m, 2H),3.32-3.36 (m, 2H), 3.46-3.55 (m, 2H), 3.90-3.95 (m, 2H), 4.00 (s, 2H),7.11 (d, J=7.63 Hz, 1H), 7.17 (t, J=8.85 Hz, 1H), 7.19-7.24 (m, 2H),7.26 (dd, J=6.41, 2.14 Hz, 1H), 7.34-7.38 (m, 1H), 7.41 (t, J=7.78 Hz,1H).

Example 6224-(4-fluoro-3-{[4-(4-methoxybenzoyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 505 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.66-1.77(m, 4H), 2.41-2.47 (m, 2H), 2.47-2.53 (m, 2H), 3.37-3.48 (m, 2H),3.55-3.67 (m, 2H), 3.67-3.77 (m, 2H), 3.77-3.82 (m, 2H), 3.83 (s, 3H),3.99 (s, 2H), 7.00 (d, J=8.85 Hz, 2H), 7.14-7.19 (m, 1H), 7.25 (dd,J=6.10, 2.14 Hz, 1H), 7.33-7.38 (m, 1H), 7.42 (d, J=8.54 Hz, 2H).

Example 6234-(4-fluoro-3-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 477 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.77(m, 4H), 2.42-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.19-3.27 (m, 2H),3.33-3.41 (m, 2H), 3.56-3.65 (m, 2H), 3.78 (s, 3H), 3.96-4.07 (m, 4H),6.93-6.94 (m, 1H), 6.95-6.97 (m, 1H), 7.16-7.18 (m, 2H), 7.19-7.21 (m,1H), 7.28 (dd, J=6.41, 2.14 Hz, 1H), 7.35-7.41 (m, 1H).

Example 6244-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 543, but was purifiedby HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flashchromatography. MS (DCI/NH₃) m/z 481 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.19-1.29(m, 1H), 1.30-1.40 (m, 2H), 1.41-1.49 (m, 2H), 1.65-1.74 (m, 7H),1.76-1.84 (m, 2H), 2.41-2.48 (m, 2H), 2.48-2.56 (m, 2H), 2.58-2.73 (m,1H), 3.33-3.43 (m, 2H), 3.52-3.62 (m, 2H), 3.64-3.72 (m, 2H), 3.72-3.85(m, 2H), 3.99 (s, 2H), 7.14-7.20 (m, 1H), 7.22-7.28 (m, 1H), 7.33-7.39(m, 1H).

Example 625N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]glycine

To a solution of EXAMPLE 493F (100 mg, 0.37 mmol) in tetrahydrofuran (5mL) was added ethyl-2-isocyanoacetate (47 mg, 0.37 mmol). The solutionwas stirred at room temperature for 16 hours and sodium hydroxide (15mg, 0.37 mmol) was added. The mixture was heated at 70° C. for 2 hoursand was concentrated. The residue was purified by HPLC (Zorbax C-18,0.1% TFA/CH₃CN/H₂O) to provide the title compound. MS (DCI/NH₃) m/z 375(M+H)⁺.

Example 626N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]leucine

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 625. MS (DCI/NH₃) m/z431 (M+H)⁺.

Example 627N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]alanine

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 625. MS (DCI/NH₃) m/z389 (M+H)⁺.

Example 628N-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]phenylalanine

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 625. MS (DCI/NH₃) m/z465 (M+H)⁺.

Example 629 ethylN-[({2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}amino)carbonyl]glycinate

To a solution of EXAMPLE 493F (2.0 g, 7.3 mmol) in a mixture oftetrahydrofuran (25 mL) and N,N-dimethylformamide (2 mL) was addedethyl-2-isocyanoacetate (0.95 g, 7.3 mmol). The mixture was stirred atroom temperature for 16 hours and was concentrated. The residue waspartitioned between ethyl acetate and brine and the organic layer waswashed with brine and concentrated. The residue was purified by flashchromatography on silica gel eluting with 70% ethyl acetate in hexanesto provide the title compound. MS (DCI/NH₃) m/z 403 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.19 (t, J=7.17 Hz, 3H), 1.52-1.63 (m, 4H), 2.29-2.40 (m,4H), 3.81 (s, 2H), 3.86 (d, J=5.80 Hz, 2H), 4.10 (q, J=7.12 Hz, 2H),6.69-6.77 (m, 1H), 6.88-6.97 (m, 1H), 7.09 (dd, J=11.29, 8.54 Hz, 1H),7.94 (dd, J=7.93, 1.83 Hz, 1H), 8.56 (br s, 1H), 12.60 (br s, 1H).

Example 6303-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione

To a solution of EXAMPLE 629 (650 mg, 1.6 mmol) in 1:1chloroform/ethanol (40 mL) was added 10N HCl (20 mL). The mixture washeated at 80° C. for 2 days and was concentrated. The residue waspurified by HPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) to yield the titlecompound as a free base. MS (DCI/NH₃) m/z 357 (M+H)⁺; ¹H NMR (CD₃OD) δ1.69-1.75 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 4.01 (s, 2H),4.15 (s, 2H), 7.18-7.20 (m, 1H), 7.21-7.25 (m, 1H), 7.31-7.35 (m, 1H).

Example 6318-(4-fluoro-3-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z478 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.48-1.83 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 2.93 (m, 2H), 2.99-3.09 (m, 2H), 3.09-3.26 (m, 2H), 3.37 (m, 2H),3.76 (m, 2H), 3.79 (s, 3H), 3.84 (s, 2H), 6.46 (s, 1H), 6.84-6.96 (m,2H), 6.94-7.05 (m, 2H), 7.18-7.30 (m, 2H), 7.30-7.38 (m, 1H), 11.97 (s,1H).

Example 6328-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z451 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.62-1.82 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.10-3.23 (m, 2H), 3.30-3.39 (m, 2H), 3.75 (m, 2H), 3.76-3.82 (m,2H), 3.84 (s, 2H), 3.86-3.94 (m, 2H), 6.45 (s, 1H), 7.16-7.31 (m, 2H),7.32-7.40 (m, 1H), 8.64 (s, 2H), 11.96 (s, 1H).

Example 6338-(3-{[4-(2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z451 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.61-1.79 (m, 2H), 2.34 (t, J=6.27 Hz,2H), 3.11-3.22 (m, 2H), 3.28 (m, 2H), 3.65 (m, 6H), 3.83 (s, 2H),4.06-4.39 (m, 2H), 5.23 (m, 1H), 6.39 (s, 1H), 6.85 (s, 4H), 7.17-7.32(m, 2H), 7.30-7.41 (m, 1H), 11.89 (s, 1H).

Example 6344-(3-{[4-(cyclopropylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 634A4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 544 (584 mg, 1.13 mmol) in 1:1dichloromethane/methanol (20 mL) was added 10% Pd/C (150 mg) undernitrogen. The suspension was purged with hydrogen, and stirred underhydrogen at room temperature for 18 hours. Solid material was filteredoff, and the filtrate was concentrated to provide the title compound. MS(DCI/NH₃) m/z 385 (M+H)⁺.

Example 634B4-(3-{[4-(cyclopropylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 634A (30 mg, 0.08 mmol) inN,N-dimethylformamide (2 mL) was added cyclopropanecarboxylic acid (6.7mg, 0.08 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC) (30 mg, 0.16 mmol), N-hydroxybenzotriazole (HOBt)(24 mg, 0.16 mmol) and triethylamine (0.02 mL, 0.16 mmol). The mixturewas stirred at room temperature for 16 hours, filtered, andconcentrated. The residue was purified by HPLC (Zorbax C-18, 0.1%TFA/CH₃CN/H₂O) to yield the title compound as a TFA salt. MS (DCI/NH₃)m/z 453 (M+H)⁺; ¹H NMR (CD₃OD) δ 0.77-0.85 (m, 4H), 0.85-0.96 (m, 1H),1.67-1.78 (m, 4H), 1.86-2.10 (m, 2H), 2.39-2.47 (m, 2H), 2.47-2.56 (m,2H), 3.34-3.50 (m, 2H), 3.54-3.68 (m, 2H), 3.74-3.79 (m, 1H), 3.79-3.88(m, 2H), 3.99 (s, 2H), 3.99-4.04 (m, 1H), 7.09-7.14 (m, 1H), 7.14-7.19(m, 1H), 7.30-7.37 (m, 1H).

Example 6354-[4-fluoro-3-({4-[(1-methylcyclopropyl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634. MS (DCI/NH₃) m/z467 (M+H)⁺; ¹H NMR (CD₃OD) δ 0.56-0.66 (m, 2H), 0.83-0.96 (m, 2H),1.26-1.32 (m, 3H), 1.53-1.66 (m, 1H), 1.67-1.78 (m, 4H), 1.95-2.06 (m,1H), 2.38-2.47 (m, 2H), 2.48-2.56 (m, 2H), 3.33-3.41 (m, 1H), 3.43-3.50(m, 1H), 3.57-3.69 (m, 2H), 3.75-3.86 (m, 2H), 3.89-3.97 (m, 2H), 3.98(s, 2H), 7.01-7.10 (m, 1H), 7.11-7.19 (m, 1H), 7.31-7.37 (m, 1H).

Example 6364-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-4-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 634. After HPLC purification, thecompound was treated with 1M HCl in ether to give the HCl salt. MS(DCI/NH₃) m/z 493 (M+H)⁺.

Example 6374-[4-fluoro-3-({4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 634. After HPLC purification, thecompound was treated with 1M HCl in ether to give the HCl salt. MS(DCI/NH₃) m/z 493 (M+H)⁺.

Example 6388-(4-fluoro-3-{[(2R),-2-phenylpiperazin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

A solution of EXAMPLE 614 (60 mg, 0.1 mmol) in tetrahydrofuran (10 mL)was treated with trifluoroacetic acid (5 mL) at room temperature for 3days and was concentrated. The residue was purified by HPLC (ZorbaxC-18, 0.1% TFA/CH₃CN/H₂O) to provide the title compound as the TFA salt.MS (DCI/NH₃) m/z 448 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.48-1.86 (m, 2H),2.14-2.42 (m, 2H), 3.02-3.37 (m, 2H), 3.40-3.73 (m, 2H), 3.87 (m, 4H),3.84 (s, 2H), 4.63 (m, 1H), 6.37 (s, 1H), 7.20-7.37 (m, 3H), 7.37-7.47(m, 2H), 7.48-7.63 (m, 3H), 9.56 (s, 1H), 11.86 (s, 1H).

Example 6398-[4-fluoro-3-({4-[(4R),-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl),benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z484 (M+H)⁺.

Example 6408-(3-{[4-(cyclopentylcarbonyl),piperazin-1-yl]carbonyl}-4-fluorobenzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z468 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.42-1.63 (m, 4H), 1.64-1.85 (m, 6H),2.35 (t, J=0.10 Hz, 2H), 2.82-3.08 (m, 1H), 3.12-3.30 (m, 4H), 3.35-3.52(m, 2H), 3.50-3.71 (m, 4H), 3.83 (s, 2H), 6.41 (s, 1H), 7.10-7.28 (m,2H), 7.28-7.51 (m, 1H), 11.92 (s, 1H).

Example 6418-[3-({4-[(5-chloropyridin-2-yl),carbonyl]piperazin-1-yl}carbonyl),-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z511 (M+H)⁺.

Example 6438-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl),carbonyl]piperazin-1-yl)}carbonyl),benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z559 (M+H)⁺.

Example 6448-(4-fluoro-3-{[4-(4-methylpiperazin-1-yl),piperidin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z469 (M+H)⁺.

Example 6458-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl),piperazin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z527 (M+H)⁺.

Example 6468-[3-({4-[(6-chloropyridin-3-yl),carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z511 (M+H)⁺.

Example 6478-{4-fluoro-3-[(4-{[1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl}piperazin-1-yl),carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z626 (M+H)⁺.

Example 6498-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl),carbonyl]piperazin-1-yl}carbonyl),benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z493 (M+H)⁺.

Example 6518-[3-({4-[(6-chloro-5-hydroxypyridin-3-yl),carbonyl]piperazin-1-yl}carbonyl),-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z527 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.60-1.79 (m, 2H), 2.34 (t, J=6.10 Hz,2H), 3.11-3.23 (m, 2H), 3.27 (m, 2H), 3.48 (m, 2H), 3.58 (m, 2H),3.63-3.73 (m, 2H), 3.82 (s, 2H), 6.43 (s, 1H), 7.18-7.29 (m, 2H),7.30-7.39 (m, 1H), 7.64 (d, J=2.03 Hz, 1H), 7.80 (d, J=2.37 Hz, 1H),11.92 (s, 1H).

Example 6548-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl),carbonyl]piperazin-1-yl}carbonyl),benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z530 (M+H)⁺.

Example 6558-(3-{[4-(1H-benzimidazol-6-ylcarbonyl),piperazin-1-yl]carbonyl}-4-fluorobenzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(H),-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z516 (M+H)⁺.

Example 6578-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z527 (M+H)⁺.

Example 6588-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z511 (M+H)⁺.

Example 659 benzyl4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}-1,4-diazepane-1-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z520 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.51 (m, 1H), 1.69 (m, 2H), 1.74-1.86 (m,1H), 2.22-2.40 (m, 2H), 3.17 (m, 2H), 3.22-3.42 (m, 2H), 3.46 (m, 4H),3.51-3.68 (m, 1H), 3.67-3.79 (m, 1H), 3.81 (s, 2H), 5.09 (s, 2H), 6.43(s, 1H), 7.07-7.43 (m, 8H), 11.68-12.04 (s, 1H).

Example 6608-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z477 (M+H)⁺.

Example 6618-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z477 (M+H)⁺.

Example 6628-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z478 (M+H)⁺.

Example 6638-(3-{[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z516 (M+H)⁺.

Example 6648-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z478 (M+H)⁺.

Example 6658-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z477 (M+H)⁺.

Example 666 ethyl4-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperazine-1-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z444 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.19 (t, J=7.14 Hz, 3H), 1.52-1.78 (m,2H), 2.35 (t, J=6.15 Hz, 2H), 3.08-3.29 (m, 4H), 3.33 (m, 2H), 3.45 (m,2H), 3.62 (m, 2H), 3.82 (s, 2H), 4.06 (q, J=7.14 Hz, 2H), 6.41 (s, 1H),6.99-7.46 (m, 3H), 11.93 (s, 1H).

Example 6678-{3-[(2,2-dimethyl-3-oxopiperazin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z414 (M+H)⁺; ¹H NMR (DMSO-d₆) δ1.68 (s, 6H), 1.71 (m, 2H), 2.34 (t,J=6.10 Hz, 2H), 3.17 (m, 4H), 3.30 (m, 2H), 3.81 (s, 2H), 6.42 (s, 1H),7.16-7.34 (m, 3H), 8.15 (s, 1H), 11.90 (s, 1H).

Example 6684-(3-{[(2R)-4-benzoyl-2-methylpiperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18. 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 489 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.17-1.33 (m, 2H),1.64-1.80 (m, 4H), 2.38-2.56 (m, 4H), 2.98-3.13 (m, 1H), 3.16-3.27 (m,1H), 3.34 (s, 3H), 3.39-3.59 (m, 1H), 3.63-3.86 (m, 1H), 3.99 (s, 2H),4.41-4.60 (m, 1H), 7.10-7.18 (m, 1H), 7.19-7.27 (m, 1H), 7.29-7.39 (m,1H), 7.41-7.55 (m, 5H).

Example 6694-(4-fluoro-3-{[4-(1,3,5-triazin-2-yl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 450 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.68-1.77 (m, 4H),2.43-2.48 (m, 2H), 2.49-2.56 (m, 2H), 3.44-3.52 (m, 2H), 3.86-3.90 (m,2H), 3.92-3.97 (m, 2H), 4.01 (s, 2H), 4.05-4.10 (m, 2H), 7.15-7.22 (m,1H), 7.27 (dd, J=6.41, 2.14 Hz, 1H), 7.33-7.42 (m, 1H), 8.61 (s, 1H),8.63 (s, 1H).

Example 6725-benzyl-3-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}imidazolidine-2,4-dione

The title compound was prepared, using the appropriate reagents, as thefree base according to the procedure for EXAMPLE 630. MS (DCI/NH₃) m/z441 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.61-1.77 (m, 4H), 2.38-2.46 (m, 2H),2.47-2.55 (m, 2H), 3.03 (dd, J=13.73, 7.32 Hz, 1H), 3.19 (dd, J=13.73,5.19 Hz, 1H), 3.90 (s, 2H), 4.57-4.66 (m, 1H), 6.74-6.80 (m, 1H), 6.99(dd, J=10.98, 8.54 Hz, 1H), 7.19-7.25 (m, 3H), 7.25-7.32 (m, 2H), 7.85(dd, J=7.63, 2.14 Hz, 1H).

Example 6734-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 673A4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents,according to the procedure for EXAMPLE 634A substituting EXAMPLE 543 forEXAMPLE 544. MS (DCI/NH₃) m/z 371 (M+H)⁺.

Example 673B4-[3-({4-[(6-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634B substitutingEXAMPLE 673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 510 (M+H)⁺; ¹H NMR(CD₃OD) δ 1.65-1.78 (m, 4H), 2.39-2.55 (m, 4H), 3.37-3.44 (m, 1H),3.46-3.52 (m, 1H), 3.53-3.59 (m, 1H), 3.63-3.70 (m, 1H), 3.73-3.78 (m,1H), 3.79-3.84 (m, 1H), 3.88 (s, 2H), 3.95-4.03 (m, 2H), 7.11-7.21 (m,1H), 7.22-7.30 (m, 1H), 7.31-7.43 (m, 1H), 7.64-7.70 (m, 1H), 7.95-8.04(m, 1H), 8.55-8.66 (m, 1H).

Example 6744-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 482 (M+H)⁺; ¹H NMR (CD₃OD) δ1.66-1.80 (m, 4H), 2.41-2.55 (m, 4H), 3.37-3.54 (m, 2H), 3.71-3.81 (m,2H), 3.83-3.95 (m, 4H), 4.00 (s, 2H), 7.13-7.22 (m, 1H), 7.23-7.30 (m,1H), 7.31-7.43 (m, 1H), 8.13 (s, 1H), 9.00-9.10 (m, 1H).

Example 6754-[4-fluoro-3-({4-[(5-oxopyrrolidin-2-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 482 (M+H)⁺.

Example 6774-{3-[(4-{[(4R)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl}piperazin-1-yl)carbonyl]-4-fluorobenzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 514 (M+H)⁺; ¹H NMR (CD₃OD) δ1.38-1.46 (m, 3H), 1.61-1.76 (m, 7H), 2.41-2.47 (m, 2H), 2.49-2.57 (m,2H), 3.36-3.49 (m, 2H), 3.53-3.64 (m, 2H), 3.66-3.77 (m, 1H), 3.84-3.93(m, 1H), 4.00 (s, 2H), 4.05-4.15 (m, 1H), 4.43-4.55 (m, 2H), 4.80-4.95(m, 2H), 7.15-7.21 (m, 1H), 7.23-7.29 (m, 1H), 7.36-7.40 (m, 1H).

Example 6784-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 465 (M+H)⁺; ¹H NMR (CD₂OD) δ1.66-1.77 (m, 4H), 2.39-2.48 (m, 2H), 2.48-2.58 (m, 2H), 3.37-3.52 (m,2H), 3.68-3.79 (m, 1H), 3.79-3.93 (m, 3H), 3.92-3.99 (m, 1H), 4.00 (s,2H), 4.04-4.16 (m, 1H), 6.63-6.71 (m, 1H), 7.13-7.21 (m, 1H), 7.23-7.29(m, 1H), 7.32-7.39 (m, 1H), 7.67-7.74 (m, 1H).

Example 6794-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 477 (M+H)⁺; ¹H NMR (CD₃OD) δ1.67-1.77 (m, 4H), 2.42-2.55 (m, 4H), 3.39-3.46 (m, 1H), 3.47-3.55 (m,1H), 3.57-3.63 (m, 1H), 3.69-3.75 (m, 1H), 3.76-3.81 (m, 1H), 3.81-3.87(m, 1H), 3.90 (s, 2H), 3.96-4.04 (m, 2H), 7.12-7.21 (m, 1H), 7.22-7.32(m, 1H), 7.31-7.40 (m, 1H), 8.58-8.76 (m, 2H), 8.89 (d, J=6.10 Hz, 1H).

Example 6804-(3-{[4-(1H-benzimidazol-5-ylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 515 (M+H)⁺.

Example 6814-[4-fluoro-3-(methylamino)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 681AN-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-2,4-dinitrobenzenesulfonamide

To a solution of EXAMPLE 493F (2.0 g, 7.3 mmol) in dichloromethane (15mL) was added 2,4-dinitrobenzene-1-sulfonyl chloride (1.95 g, 7.3 mmol)and pyridine (0.7 mL, 8.8 mmol). The mixture was stirred at roomtemperature for 16 hours and was concentrated. The residue waspartitioned between ethyl acetate and water and the organic layercollected and concentrated. The residue was purified by flashchromatography eluting with 60% ethyl acetate in hexanes to provide thetitle compound. MS (DCI/NH₃) m/z 504 (M+H)⁺.

Example 681BN-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)-N-methyl-2,4-dinitrobenzenesulfonamide

To a solution of EXAMPLE 681A (1.4 g, 2.8 mmol) in N,N-dimethylformamide(8 mL) was added methyl iodide (0.21 mL, 3.3 mmol) and potassiumcarbonate (1.92 g, 13.9 mmol). The mixture was stirred at roomtemperature for 16 hours and was concentrated. The residue waspartitioned between ethyl acetate and water and the organic layerconcentrated. The residue was purified by flash chromatography elutingwith 60% ethyl acetate in hexanes to provide the title compound. MS(DCI/NH₃) m/z 518 (M+H)⁺.

Example 681C4-[4-fluoro-3-(methylamino)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of EXAMPLE 681B (940 mg, 1.8 mmol) in dichloromethane (15mL) was added thioglycolic acid (0.16 mL, 2.4 mmol) and triethylamine(0.5 mL, 3.6 mmol). The mixture was stirred at ambient temperature for 5minutes and washed with brine. The organic layer was concentrated andthe residue purified by flash chromatography on silica gel eluting with5% methanol in dichloromethane to provide the title compound. MS(DCI/NH₃) m/z 288 (M+H)⁺.

Example 6828-{4-fluoro-3-[(4-isonicotinoyl-1,4-diazepan-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺.

Example 6838-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺.

Example 6848-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺.

Example 6858-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z492 (M+H)⁺.

Example 6868-(3-{[4-(1H-benzimidazol-6-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-fluorobenzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z530 (M+H)⁺.

Example 6878-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z541 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56-2.00 (m, 4H), 2.27-2.42 (m, 2H),3.10-3.25 (m, 2H), 3.30-3.45 (m, 1H), 3.44-3.67 (m, 3H), 3.67-3.93 (m,6H), 6.47 (m, 1H), 6.97-7.43 (m, 3H), 7.49-7.72 (m, 3H), 7.71-8.00 (m,1H), 7.96-8.12 (m, 1H), 8.29-8.73 (m, 1H), 11.93 (s, 0.5H), 11.99 (s,0.5H).

Example 6888-(4-fluoro-3-{[4-(quinolin-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z541 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.51-1.81 (m, 4H), 2.21-2.42 (m, 2H),3.04-3.26 (m, 3H), 3.39 (m, 2H), 3.49 (m, 2H), 3.60-3.70 (m, 1H), 3.75(m, 2H), 3.84 (s, 1H), 3.87 (s, 1H), 6.49 (s, 1H), 7.07-7.41 (m, 3H),7.60-7.77 (m, 1H), 7.78-7.97 (m, 1H), 7.97-8.16 (m, 2H), 8.48 (s, 0.5H),8.50 (s, 0.5H), 8.92 (s, 0.5H), 8.94 (s, 0.5H), 11.97 (s, 0.5H), 11.99(s, 0.5H).

Example 6898-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z544 (M+H)⁺.

Example 6908-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z573 (M+H)⁺.

Example 6918-(4-fluoro-3-{[4-(4-fluorobenzoyl)piperidin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z493 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.35-1.59 (m, 2H), 1.60-1.81 (m, 3H),1.91 (m, 1H), 2.33 (m, 2H), 2.90-3.07 (m, 1H), 3.07-3.31 (m, 3H), 3.45(m, 1H), 3.65-3.82 (m, 1H), 3.82 (s, 2H), 4.52 (m, 1H), 6.41 (s, 1H),6.89-7.32 (m, 3H), 7.37 (t, J=8.92 Hz, 2H), 8.10 (dd, J=8.72, 5.55 Hz,2H), 11.89 (s, 1H).

Example 6928-[3-({4-[(5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z515 (M+H)⁺.

Example 6938-(4-fluoro-3-{[4-(pyrazin-2-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z492 (M+H)⁺.

Example 6948-(4-fluoro-3-{[4-(2-furoyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z480 (M+H)⁺.

Example 6958-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z449 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.52-1.80 (m, 2H), 2.35 (t, J=6.10 Hz,2H), 3.18 (m, 2H), 3.39 (m, 4H), 3.47-3.61 (m, 2H), 3.76-3.84 (m, 2H),3.84 (s, 2H), 6.44 (s, 1H), 7.05-7.33 (m, 2H), 7.30-7.48 (m, 1H), 7.82(dd, J=8.98, 5.26 Hz, 1H), 8.02 (dd, J=8.81, 2.37 Hz, 1H), 8.24 (d,J=5.42 Hz, 1H), 8.46 (d, J=2.71 Hz, 1H), 11.92 (s, 1H).

Example 6968-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z450 (M+H)⁺.

Example 6978-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z400 (M+H)⁺.

Example 698 tert-butyl4-[{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}(methyl)amino]piperidine-1-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z500 (M+H)⁺.

Example 699 tert-butyl4-({2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}amino)piperidine-1-carboxylate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z486 (M+H)⁺.

Example 700 tert-butyl1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-ylcarbamate

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z486 (M+H)⁺)⁺; ¹H NMR (DMSO-d₆) 1.20-1.30 (m, 1H), 1.38 (s, 9H),1.59-1.74 (m, 3H), 1.78 (m, 1H), 2.34 (t, J=6.10 Hz, 2H), 2.85-2.99 (m,2H), 3.03-3.12 (m, 1H), 3.17 (m, 2H), 3.35 (m, 1H), 3.50 (m, 1H), 3.81(s, 2H), 4.33 (m, 1H), 6.42 (s, 1H), 7.13-7.26 (m, 2H), 7.26-7.38 (m,1H), 7.95 (s, 1H), 11.90 (s, 1H).

Example 7018-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]-1,4-diazepan-1-yl}carbonyl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m z501 (M+H)⁺.

Example 7028-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z480 (M+H)⁺.

Example 7038-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)-1,4-diazepan-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z497 (M+H)⁺.

Example 7048-(4-fluoro-3-{[4-(1H-pyrazol-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z466 (M+H)⁺.

Example 7058-(4-fluoro-3-{[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z483 (M+H)⁺)⁺; ¹H NMR (DMSO-d₆) δ 1.71-1.92 (m, 2H), 2.53 (t, J=6.10 Hz,2H), 3.46 (m, 2H), 3.70-3.83 (m, 4H), 3.88 (m, 4H), 3.93 (s, 2H), 7.16(t, J=8.98 Hz, 1H), 7.29 (dd, J=6.27, 1.86 Hz, 1H), 7.32-7.46 (m, 1H),8.13 (d, J=1.70 Hz, 1H), 9.05 (s, 1H).

Example 7062-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH₃) m/z400 (M+H)⁺.

Example 7072-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-piperidin-4-ylbenzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH₃) m/z466 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.71-1.91 (m, 4H), 2.20 (dd, J=14.07, 3.22Hz, 2H), 2.51 (t, —6.27 Hz, 2H), 3.07-3.22 (m, 2H), 3.22-3.30 (m, 2H),3.37-3.49 (m, 4H), 4.03-4.29 (m, 1H), 7.14 (dd, J=10.51, 8.48 Hz, 1H),7.33-7.48 (m, 1H), 7.51 (dd, J=6.78, 2.37 Hz, 1H).

Example 7088-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-fluorobenzyl}-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 638. MS (DCI/NH₃) m/z386 (M+H)⁺.

Example 7092-fluoro-N-(4-hydroxycyclohexyl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z401 (M+H)⁺.

Example 7102-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z505 (M+H)⁺.

Example 711 tert-butyl2-(ethyl{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethylcarbamate

To a solution of EXAMPLE 492F (500 mg, 1.654 mmol) in anhydrousN,N-dimethylformamide (15 mL) was added N-Boc-N′-ethyl-1,2-ethylenediamine hydrochloride (446 mg, 1.985 mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC)(476 mg, 2.481 mmol), 1-hydroxybenzotriazole monohydrate (380 mg, 2.481mmol), and triethylamine (0.807 mL, 5.79 mmol). The mixture was stirredat ambient temperature overnight and was partitioned between ethylacetate and brine. The organic phase was washed with brine and water andconcentrated. The residue was purified by flash chromatography (ethylacetate) to give the title compound. MS (DCI/NH₃) m/z 473 (M+H)⁺; ¹H NMR(CDCl₃) δ 1.07 (t, J=7.21 Hz, 3H), 1.45 (s, 9H), 1.71 (m, 4H), 2.33-2.42(m, 2H), 2.55-2.62 (m, 2H), 3.17-3.29 (m, 2H), 3.38-3.45 (m, 2H),3.58-3.64 (m, 2H), 3.87-3.91 (m, 2H), 5.06 (s, 1H), 6.98-7.05 (m, 1H),7.13-7.19 (m, 2H), 11.34 (s, 1H).

Example 7122-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z505 (M+H)⁺.

Example 713N-[1-(1H-benzimidazol-5-ylcarbonyl)piperidin-4-yl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z530 (M+H)⁺.

Example 7142-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide

To a solution of EXAMPLE 492F (102 mg, 0.337 mmol) in anhydrousN,N-dimethylformamide (8 mL) was added 1-(2-aminoethyl)pyrrolidin-2-onehydrochloride (83 mg, 0.506 mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (97mg, 0.506 mmol), 1-hydroxybenzotriazole monohydrate (78 mg, 0.506 mmol),and triethylamine (0.165 mL, 3.5 mmol). The mixture was stirred atambient temperature overnight, and was partitioned between ethyl acetateand brine. The organic phase was washed with brine and water andconcentrated. The residue was purified by flash chromatography (15%methanol in 2:1 ethyl acetate/hexane) to provide the title compound. MS(DCI/NH₃) m/z 413 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.71 (t, J=2.90 Hz, 4H),1.99-2.05 (m, 2H), 2.33 (t, J=8.09 Hz, 2H), 2.44 (m, 2H), 2.50 (m, 2H),3.49 (t, J=5.49 Hz, 2H), 3.52-3.57 (m, 4H), 3.99 (s, 2H), 7.13 (dd,J=10.37, 8.54 Hz, 1H), 7.33-7.38 (m, 1H), 7.51 (dd, J=6.71, 2.14 Hz,1H).

Example 7152-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z494 (M+H)⁺.

Example 7162-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z515 (M+H)⁺.

Example 7172-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z511 (M+H)⁺.

Example 7182-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z494 (M+H)⁺.

Example 719N-(2-aminoethyl)-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

A solution of EXAMPLE 711 (662 mg, 1.40 mmol) in 20 mL of methylenechloride was treated with trifluoroacetic acid (5 mL) at ambienttemperature for 1 hour. Toluene (10 mL) was added and the solutionconcentrated. The residue was dissolved in methylene chloride andmethanol, and treated with an access of 2M HCl in ether. Concentrationprovided the title compound as the HCl salt. MS (DCI/NH₃) m/z 373(M+H)⁺; ¹H NMR (CD₃OD) δ 1.10 (t, J=7.02 Hz, 3H), 1.71-1.78 (m, 4H),2.47-2.50 (m, 2H), 2.55 (m, 2H), 3.24 (t, J=6.41 Hz, 2H), 3.29-3.33 (m,2H), 3.80 (t, J=6.41 Hz, 2H), 4.08 (s, 2H), 7.19 (t, J=9.00 Hz, 1H),7.29-7.32 (m, 1H), 7.36-7.40 (m, 1H).

Example 7204-{4-fluoro-3-[(4-isonicotinoylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 476 (M+H)⁺; ¹H NMR (CD₃OD) δ1.66-1.79 (m, 4H), 2.41-2.55 (m, 4H), 3.34-3.41 (m, 2H), 3.46-3.56 (m,2H), 3.74-3.83 (m, 2H), 3.85-3.93 (m, 2H), 3.95-4.05 (m, 2H), 7.11-7.21(m, 1H), 7.22-7.30 (m, 1H), 7.32-7.44 (m, 1H), 7.75-7.81 (m, 1H),7.82-7.91 (m, 1H), 8.76-8.89 (m, 2H).

Example 7212-fluoro-N-methyl-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m z505 (M+H)⁺.

Example 7224-(4-fluoro-3-{[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 476 (M+H)⁺; ¹H NMR (CD₃OD) δ1.66-1.79 (m, 4H), 2.40-2.47 (m, 2H), 2.48-2.57 (m, 2H), 3.38-3.51 (m,2H), 3.51-3.63 (m, 2H), 3.75-3.84 (m, 2H), 3.85-3.95 (m, 2H), 4.00 (s,2H), 7.11-7.22 (m, 1H), 7.22-7.29 (m, 1H), 7.30-7.42 (m, 1H), 7.71-7.85(m, 1H), 8.17-8.30 (m, 1H), 8.72-8.87 (m, 2H).

Example 7234-[3-({4-[(5-chloro-6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 526 (M+H)⁺.

Example 7242-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺.

Example 7254-{4-fluoro-3-[(4-{[1-isopropyl-2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbonyl}piperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 625 (M+H)⁺; ¹H NMR (CD₃OD) δ1.65-1.73 (m, 4H), 1.74 (d, J=7.02 Hz, 6H), 2.39-2.47 (m, 2H), 2.47-2.57(m, 2H), 3.40-3.70 (m, 4H), 3.73-3.95 (m, 4H), 3.99 (s, 2H), 4.93-5.17(m, 1H), 7.13-7.21 (m, 1H), 7.22-7.29 (m, 1H), 7.31-7.39 (m, 1H), 7.55(d, J=8.54 Hz, 1H), 7.92 (s, 1H), 8.00 (d, J=8.54 Hz, 1H).

Example 7262-fluoro-N-[1-(2-furoyl)piperidin-4-yl]-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z480 (M+H)⁺.

Example 7274-[4-fluoro-3-({4-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 486 (M+H)⁺; ¹H NMR (CD₃OD) δ1.68-1.77 (m, 4H), 2.42-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.12-3.23 (m,1H), 3.37-3.50 (m, 2H), 3.54-3.64 (m, 2H), 3.65-3.73 (m, 3H), 3.77-3.95(m, 3H), 4.36-4.43 (m, 1H), 4.44-4.51 (m, 1H), 4.89-5.01 (m, 2H),7.15-7.20 (m, 1H), 7.23-7.28 (m, 1H), 7.36-7.40 (m, 1H).

Example 7284-[4-fluoro-3-({4-[(1-isopropyl-1H-1,2,3-benzotriazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 558 (M+H)⁺; ¹H NMR (CD₃OD) δ1.65-1.75 (m, 4H), 1.73 (d, J=6.71 Hz, 6H), 2.41-2.47 (m, 2H), 2.48-2.54(m, 2H), 3.43-3.67 (m, 4H), 3.69-3.94 (m, 4H), 3.99 (s, 2H), 5.21-5.30(m, 1H), 7.12-7.20 (m, 1H), 7.23-7.29 (m, 1H), 7.31-7.40 (m, 1H), 7.63(d, J=8.85 Hz, 1H), 7.93 (d, J=8.54 Hz, 1H), 8.12 (s, 1H).

Example 7292-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-{1-[(4R)-1,3-thiazolidin-4-ylcarbonyl]piperidin-4-yl}benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z501 (M+H)⁺.

Example 7304-(4-fluoro-3-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 476 (M+H)⁺; ¹H NMR (CD₃OD) δ1.64-1.78 (m, 4H), 2.39-2.56 (m, 4H), 3.36-3.43 (m, 1H), 3.46-3.55 (m,2H), 3.57-3.67 (m, 1H), 3.72-3.85 (m, 2H), 3.90 (s, 2H), 3.96-4.05 (m,2H), 7.09-7.20 (m, 1H), 7.22-7.30 (m, 1H), 7.31-7.41 (m, 1H), 7.49-7.59(m, 1H), 7.68 (t, J=8.70 Hz, 1H), 7.94-8.07 (m, 1H), 8.61 (dd, J=27.46,3.97 Hz, 1H).

Example 7312-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z497 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.34-1.59 (m, 2H), 1.62-1.75 (m, 2H),1.89 (m, 2H), 2.33 (t, J=6.10 Hz, 2H), 2.92-3.10 (m, 1H), 3.10-3.22 (m,2H), 3.20-3.31 (m, 1H), 3.81 (s, 2H), 3.93-4.21 (m, 2H), 4.35 (d, J=1.70Hz, 1H), 6.38 (s, 1H), 7.19 (dd, J=10.17, 8.48 Hz, 1H), 7.24-7.38 (m,1H), 7.36-7.54 (m, 1H), 8.14 (d, J=1.70 Hz, 1H), 8.32 (d, J=7.46 Hz,1H), 9.17 (d, J=2.03 Hz, 1H), 11.85 (s, 1H).

Example 7334-(4-fluoro-3-{[4-(pyrimidin-5-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 477 (M+H)⁺; ¹H NMR (CD₃OD) δ1.66-1.78 (m, 4H), 2.40-2.48 (m, 2H), 2.48-2.55 (m, 2H), 3.41-3.53 (m,3H), 3.58-3.66 (m, 1H), 3.77-3.91 (m, 4H), 4.00 (s, 2H), 7.10-7.20 (m,1H), 7.23-7.31 (m, 1H), 7.31-7.42 (m, 1H), 8.85-8.95 (m, 2H), 9.24 (s,1H).

Example 7342-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z480 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.31-1.56 (m, 2H), 1.60-1.75 (m, 2H),1.77-1.96 (m, 2H), 2.24-2.39 (m, 2H), 3.00-3.23 (m, 6H), 3.82 (s, 2H),4.17-4.62 (m, 1H), 6.40 (s, 1H), 6.54 (d, J=2.37 Hz, 1H), 6.97 (d,J=3.39 Hz, 1H), 7.14-7.25 (m, 1H), 7.28-7.39 (m, 1H), 7.44 (dd, J=6.95,2.20 Hz, 1H), 7.78 (d, J=2.03 Hz, 1H), 8.30 (d, J=7.46 Hz, 1H), 11.87(s, 1H).

Example 7354-[4-fluoro-3-({4-[(6-hydroxypyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 492 (M+H)⁺.

Example 7362-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺.

Example 7382-fluoro-N-(1-isonicotinoylpiperidin-4-yl)-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z491 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.44-1.74 (m, 2H), 1.75-1.89 (m, 2H),1.97 (m, 1H), 2.02-2.21 (m, 1H), 2.51 (t, J=6.27 Hz, 2H), 3.01-3.21 (m,1H), 3.22-3.32 (m, 3H), 3.58 (m, 1H), 3.92 (s, 2H), 4.03-4.28 (m, 1H),4.57 (m, 1H), 7.14 (dd, J=10.34, 8.65 Hz, 1H), 7.26-7.45 (m, 1H), 7.53(dd, J=6.78, 2.03 Hz, 1H), 7.82 (d, J=6.44 Hz, 2H), 8.84 (d, J=5.76 Hz,2H).

Example 7394-(4-fluoro-3-{[4-(quinolin-2-ylcarbonyl)piperazin-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 526 (M+H)⁺; ¹H NMR (CD₃OD) δ1.61-1.78 (m, 4H), 2.38-2.56 (m, 4H), 3.41-3.48 (m, 1H), 3.50-3.57 (m,1H), 3.57-3.62 (m, 1H), 3.66-3.74 (m, 1H), 3.82-3.90 (m, 2H), 3.95 (s,2H), 3.96-3.99 (m, 1H), 4.00-4.05 (m, 1H), 7.09-7.22 (m, 1H), 7.23-7.30(m, 1H), 7.31-7.43 (m, 1H), 7.64-7.76 (m, 2H), 7.79-7.90 (m, 1H),7.96-8.03 (m, 1H), 8.04-8.13 (m, 1H), 8.46-8.55 (m, 1H).

Example 740N-[(1S,2S)-2-aminocyclohexyl]-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z400 (M+H)⁺.

Example 742N-[2-(benzoylamino)ethyl]-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

To a suspension of EXAMPLE 719 as the HCl salt (65 mg, 0.134 mmol) in amixture of tetrahydrofuran (2 mL) and acetonitrile (2 mL) was added2,5-dioxopyrrolidin-1-yl benzoate (44 mg, 0.201 mmol) and triethylamine(0.056 mL, 0.403 mmol). The solution was heated at 60° C. overnight.After concentration, the residue was purified by HPLC (Zorbax, C-18,250×2.54 column, Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN:0-100% gradient) to provide the title compound as the TFA salt. MS(DCI/NH₃) m/z 477 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.08 (t, J=7.20 Hz, 3H),1.66-1.72 (m, 4H), 2.32-2.40 (m, 2H), 2.43-2.51 (m, 2H), 3.27-3.32 (m,2H), 3.38-3.45 (m, 2H), 3.68-3.72 (m, 2H), 3.94 (s, 2H), 7.01-7.30 (m,5H), 7.11-7.15 (m, 1H), 7.43-7.47 (m, 1H), 7.80-7.83 (m, 1H).

Example 743N-[2-(ethyl{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethyl]pyrrolidine-1-carboxamide

To a suspension of EXAMPLE 719 as the HCl salt (65 mg, 0.134 mmol) in amixture of tetrahydrofuran (2 mL) and acetonitrile (2 mL) was addedtriethylamine (0.056 mL, 0.403 mmol) and 1-pyrrolidinecarbonyl chloride(0.030 mL, 0.269 mmol). The solution was heated at 60° C. overnight.After concentration, the residue was purified by HPLC (Zorbax, C-18,250×2.54 column, Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN;0-100% gradient) to provide the title compound. MS (DCI/NH₃) m/z 470(M+H)⁺; ¹H NMR (CD₃OD) δ 1.05 (t, J=7.02 Hz, 2H), 1.24 (t, J=7.17 Hz,1H), 1.69-1.74 (m, 4H), 1.88-1.92 (m, 4H), 2.42-2.46 (m, 2H), 2.49-2.52(m, 2H), 3.17-3.26 (m, 4H), 3.28-3.35 (m, 2H), 3.45 (t, J=6.26 Hz, 2H),3.65 (t, J=6.26 Hz, 2H), 3.98 (s, 1H), 3.99 (s, 1H), 7.11 (t, J=9.00 Hz,1H), 7.15-7.20 (m, 1H), 7.27-7.35 (m, 1H).

Example 7452-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]-N-(1-pyridin-2-ylpiperidin-4-yl)benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 506. MS (DCI/NH₃) m/z463 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.56 (q, J=10.5 Hz, 2H), 1.65-1.74 (m,2H), 1.95 (dd, J=13.09, 3.17 Hz, 2H), 2.34 (t, J=6.15 Hz, 2H), 2.75 (d,J=4.36 Hz, 1H), 3.26 (t, J=11.70 Hz, 2H), 3.82 (s, 2H), 4.07-4.21 (m,3H), 6.38 (s, 1H), 6.83 (t, J=6.35 Hz, 1H), 7.15-7.29 (m, 2H), 7.32-7.39(m, 1H), 7.44 (dd, J=6.94, 2.18 Hz, 1H), 7.85 (t, J=7.73 Hz, 1H), 8.04(dd, J=5.75, 1.78 Hz, 1H), 8.28 (d, J=7.54 Hz, 1H), 11.86 (s, 1H).

Example 746N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)pyridine-2-carboxamideExample 746A tert-butyl1-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazin-8-yl)methyl)benzoyl)piperidin-4-ylcarbamate

To a solution of EXAMPLE 506F (400 mg, 1.32 mmol) in anhydrousN,N-dimethylformamide (20 mL) was added tert-butylpiperidin-4-ylcarbamate (264 mg, 1.32 mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC)(327 mg, 1.72 mmol), 1-hydroxybenzotriazole monohydrate (264 mg, 1.72mmol), and triethylamine (173 mg, 1.72 mmol). The reaction mixture wasstirred at ambient temperature overnight, and partitioned betweenmethylene chloride and brine. The organic phase was washed with brine,water, and concentrated. The residue was purified by HPLC (Zorbax, C-18,250×2.54 column, Mobile phase A: 0.1% TFA in H₂O: B: 0.1% TFA in CH₃CN;0-100% gradient) to provide the title compound as TFA salt. MS (DCI/NH₃)m/z 486 (M+H)⁺.

Example 746B 8-(3-(4-aminopiperidine-1carbonyl)-4-fluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyridazin-5(6H)-one

A solution of EXAMPLE 746A (1.5 g) in tetrahydrofuran (15 mL) wastreated with trifluoroacetic acid (2 mL) at 60° C. overnight andconcentrated. The residue was purified by HPLC (Zorbax, C-18, 250×2.54column. Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN; 0-100%gradient) to provide the title compound as TFA salt. MS (DCI/NH₃) m/z386 (M+H)⁺.

Example 746CN-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)pyridine-2-carboxamide

To a solution of EXAMPLE 746B (50 mg, 0.13 mmol) in anhydrousN,N-dimethylformamide (4 mL) was added picolinic acid (20 mg, 0.17mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(EDC) (32 mg, 0.17 mmol), 1-hydroxybenzotriazole monohydrate (26 mg,0.17 mmol), and triethylamine (17 mg, 0.17 mmol). The mixture was heateduntil homogeneous and stirred at ambient temperature overnight. Themixture was partitioned between methylene chloride and brine. Theorganic phase was washed with brine, water, and concentrated. Theresidue was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobilephase A: 0.1% TFA in H₂O; B: 0.1% TFA in CH₃CN; 0-100% gradient) toprovide the title compound. MS (DCI/NH₃) m/z 491 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.53-1.78 (m, 5H), 1.84-1.92 (m, 1H), 2.35 (t, J=6.27 Hz,2H), 2.88-2.99 (m, 1H), 3.11-3.24 (m, 4H), 3.42 (d, J=13.90 Hz, 1H),3.83 (s, 2H), 4.05-4.14 (m, 1H), 4.49 (d, J=13.22 Hz, 1H), 6.42 (s, 1H),7.18-7.35 (m, 2H), 7.56-7.63 (m, 1H), 7.95-8.06 (m, 2H), 8.64 (d, J=4.07Hz, 2H), 11.91 (s, 1H).

Example 747N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)nicotinamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z491 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.41-1.60 (m, 2H), 1.65-1.75 (m, 2H),1.83 (d, J=10.31 Hz, 1H), 1.94 (d, J=11.90 Hz, 1H), 2.35 (t, J=6.15 Hz,2H), 2.99 (t, J=11.30 Hz, 1H), 3.13-3.23 (m, 3H), 3.44 (d, J=13.48 Hz,1H), 3.84 (s, 2H), 4.05-4.15 (m, 1H), 4.46 (d, J=13.48 Hz, 1H), 6.42 (s,1H), 7.18-7.27 (m, 2H), 7.30-7.36 (m, 1H), 7.59 (dd, J=7.93, 5.16 Hz,1H), 8.28 (d, J=8.33 Hz, 1H), 8.58 (d, J=7.54 Hz, 1H), 8.75 (dd, J=5.16,1.59 Hz, 1H), 9.03 (d, J=11.98 Hz, 1H), 11.92 (s, 1H).

Example 748N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)isonicotinamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z491 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.40-1.60 (m, 2H), 1.66-1.73 (m, 2H),1.78-1.85 (m, 1H), 1.93 (d, J=10.51 Hz, 1H), 2.35 (t, J=6.27 Hz, 2H),2.93-3.03 (m, 1H), 3.12-3.23 (m, 3H), 3.43 (d, J=13.56 Hz, 1H), 3.83 (s,2H), 4.04-4.15 (m, 1H), 4.46 (d, J=12.89 Hz, 1H), 6.40 (s, 1H),7.19-7.25 (m, 2H), 7.31-7.35 (m, 1H), 7.82-7.88 (m, 2H), 8.68 (d, J=7.46Hz, 1H), 8.74-8.80 (m, 2H), 11.91 (s, 1H).

Example 749N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-indazole-6-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z530 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.45-1.59 (m, 2H), 1.65-1.73 (m, 2H),1.78-1.87 (m, 1H), 1.94 (d, J=10.17 Hz, 1H), 2.34 (t, J=6.10 Hz, 2H),2.91-3.03 (m, 1H), 3.15-3.22 (m, 3H), 3.45 (d, J=13.22 Hz, 1H), 3.83 (s,2H), 4.07-4.18 (m, 1H), 4.50 (d, J=12.88 Hz, 1H), 6.41 (s, 1H),7.18-7.27 (m, 2H), 7.33 (dd, J=5.26, 1.86 Hz, 1H), 7.82 (d, J=8.81 Hz,1H), 7.96 (dd, J=8.48, 1.36 Hz, 1H), 8.26 (s, 1H), 8.50-8.57 (m, 1H),9.23 (s, 1H), 11.89 (s, 1H).

Example 750N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-2-furamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z480 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.40-1.58 (m, 2H), 1.66-1.77 (m, 3H),1.86 (d, J=10.51 Hz, 1H), 2.34 (t, J=6.10 Hz, 2H), 2.86-2.96 (m, 1H),3.09-3.22 (m, 3H), 3.41 (d, J=12.54 Hz, 1H), 3.83 (s, 2H), 3.99-4.08 (m,1H), 4.48 (d, J=13.22 Hz, 1H), 6.43 (s, 1H) 6.61 (dd, J=3.39, 1.70 Hz,1H), 7.10 (d, J=3.73 Hz, 1H), 7.18-7.27 (m, 2H), 7.29-7.36 (m, 1H), 7.83(s, 1H), 8.28 (s, 1H), 11.92 (s, 1H).

Example 751N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1,3-thiazole-4-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z497 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.50-1.62 (m, 1H), 1.63-1.78 (m, 3H),1.86 (d, J=10.31 Hz, 1H), 2.35 (t, J=6.15 Hz, 2H), 2.87-2.97 (m, 1H),3.11-3.22 (m, 2H), 3.41 (d, J=13.09 Hz, 1H), 3.83 (s, 2H), 4.04-4.13 (m,1H), 4.49 (d, J=13.09 Hz, 2H), 6.40 (s, 1H), 7.17-7.25 (m, 2H),7.28-7.36 (m, 1H), 8.32 (d, J=1.98 Hz, 1H), 8.37 (s, 1H), 9.17 (d,J=1.98 Hz, 1H), 11.90 (s, 1H).

Example 753N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]phenyl}-N-methylcyclobutanecarboxamide

To a solution of EXAMPLE 681C (40 mg, 0.14 mmol) inN,N-dimethylformamide (3 mL) was added (cyclobutanecarboxylic acid (14mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC) (53 mg, 0.28 mmol). N-hydroxybenzotriazole (HOBt)(38 mg, 0.28 mmol), and triethylamine (28 mg, 0.28 mmol). The reactionmixture was stirred at ambient temperature for 16 hours and wasconcentrated. The residue was purified by HPLC (Zorbax C-18, 0.1%TFA/CH₃CN/H₂O) to provide the title compound (13 mg, 25%). MS (DCI/NH₃)m/z 370 (M+H)⁺.

Example 7544-[4-fluoro-3-({4-[(2-methyl-1H-benzimidazol-5-yl)carbonyl]piperazin-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 529 (M+H)⁺; ¹H NMR (CD₃OD) δ1.64-1.80 (m, 4H), 2.40-2.47 (m, 2H), 2.47-2.56 (m, 2H), 2.88 (s, 3H),3.39-3.68 (m, 4H), 3.71-3.94 (m, 4H), 3.99 (s, 2H), 7.12-7.21 (m, 1H),7.22-7.27 (m, 1H), 7.34-7.41 (m, 1H), 7.64 (d, J=8.24 Hz, 1H), 7.82 (d,J=8.54 Hz, 1H), 7.84 (s, 1H).

Example 7554-[3-({4-[(2-chloropyridin-3-yl)carbonyl]piperazin-1-yl}carbonyl)-4-fluorobenzyl]-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 510 (M+H)⁺; ¹H NMR (CD₃OD) δ1.65-1.81 (m, 4H), 2.39-2.56 (m, 4H), 3.22-3.28 (m, 1H), 3.35-3.46 (m,2H), 3.46-3.54 (m, 1H), 3.73-3.86 (m, 2H), 3.90 (s, 2H), 3.95-4.04 (m,2H), 7.10-7.22 (m, 1H), 7.26 (d, J=9.76 Hz, 1H), 7.30-7.40 (m, 1H),7.44-7.54 (m, 1H), 7.82-7.92 (m, 1H), 8.42-8.52 (m, 1H).

Example 7564-{4-fluoro-3-[(4-pyridin-3-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 448 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.67-1.79 (m, 4H),2.41-2.49 (m, 2H), 2.49-2.57 (m, 2H), 3.41-3.50 (m, 2H), 3.52-3.63 (m,4H), 3.91-3.98 (m, 2H), 4.01 (s, 2H), 7.19 (t, J=9.00 Hz, 1H), 7.27 (dd,J=6.26, 2.29 Hz, 1H), 7.36-7.42 (m, 1H), 7.85 (dd, J=9.00, 5.34 Hz, 1H),8.08-8.13 (m, 1H), 8.16 (d, J=5.49 Hz, 1H), 8.39 (d, J=2.75 Hz, 1H).

Example 7574-{4-fluoro-3-[(4-pyrimidin-5-ylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 543, but was purified byHPLC (Zorbax C-18, 0.1% TFA/CH₃CN/H₂O) instead of flash chromatography.MS (DCI/NH₃) m/z 449 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.66-1.80 (m, 4H),2.41-2.48 (m, 2H), 2.48-2.56 (m, 2H), 3.33-3.39 (m, 2H), 3.41-3.50 (m,2H), 3.50-3.67 (m, 2H), 3.90-3.98 (m, 2H), 4.00 (s, 2H), 7.13-7.23 (m,1H), 7.24-7.31 (m, 1H), 7.34-7.43 (m, 1H), 8.52 (s, 2H), 8.61 (s, 1H).

Example 758N-(1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]benzoyl}piperidin-4-yl)-1H-pyrazole-4-carboxamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 746C. MS (DCI/NH₃) m/z480 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.43-1.59 (m, 2H), 1.65-1.77 (m, 3H),1.83-1.90 (m, 1H), 2.34 (t, J=6.27 Hz, 2H), 2.87-2.97 (m, 1H), 3.10-3.22(m, 2H), 3.40 (d, J=13.22 Hz, 1H), 3.83 (s, 2H), 4.00-4.10 (m, 1H), 4.47(d, J=13.22 Hz, 1H), 6.39 (s, 1H), 6.67 (d, J=2.03 Hz, 1H), 7.17-7.26(m, 3H), 7.29-7.34 (m, 1H), 7.74 (d, J=2.03 Hz, 1H), 8.04 (s, 1H), 11.89(s, 1H).

Example 7594-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 634 substituting EXAMPLE673A for EXAMPLE 634A. MS (DCI/NH₃) m/z 399 (M+H)⁺; ¹H NMR (CD₂OD) δ1.66-1.78 (m, 4H), 2.39-2.48 (m, 2H), 2.48-2.56 (m, 2H), 2.99 (d, J=5.49Hz, 3H), 3.39 (t, J=5.19 Hz, 1H), 3.49 (t, J=5.49 Hz, 1H), 3.60 (t,J=5.19 Hz, 1H), 3.91-4.00 (m, 2H), 4.00 (s, 2H), 4.27-4.36 (m, 1H),7.14-7.21 (m, 1H), 7.25-7.29 (m, 1H), 7.36-7.40 (m, 1H).

Example 761N-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

To a suspension of EXAMPLE 719 as the HCl salt (59 mg, 0.134 mmol) inanhydrous pyridine (2 mL) was added cyclopropanecarbonyl chloride (0.018mL, 0.20 mmol). This solution was stirred at ambient temperatureovernight and concentrated. The residue was purified by HPLC (Zorbax,C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H₂O; B: 0.1% TFA inCH₃CN; 0-100% gradient) to provide the title compound as the TFA salt.MS (DCI/NH₃) m/z 441 (M+H)⁺; ¹H NMR (CD₃OD) δ 0.72-0.77 (m, 3H),0.81-0.85 (m, 1H), 1.05 (t, J=7.02 Hz, 2H), 1.24 (t, J=7.17 Hz, 1H),1.52-1.57 (m, 1H), 1.71 (t, J=2.75 Hz, 4H), 2.43-2.47 (m, J=1.83 Hz,2H), 2.48-2.52 (m, J=1.53 Hz, 2H), 3.24 (t, J=7.17 Hz, 2H), 3.29-3.34(m, 2H), 3.49 (t, J=6.56 Hz, 1H), 3.63 (t, J=6.41 Hz, 2H), 3.99 (s, 2H),7.10-7.20 (m, 2H), 7.28-7.33 (m, 1H).

Example 762N-{2-[(2,6-difluorobenzoyl)amino]ethyl}-N-ethyl-2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzamide

The title compound was prepared, using the appropriate reagents, as theTFA salt according to the procedure for EXAMPLE 761. MS (DCI/NH₃) m/z513 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.03-1.10 (m, 2H), 1.22-1.29 (m, 1H),1.66-1.73 (m, 4H), 2.44 (d, J=2.44 Hz, 2H), 2.47-2.51 (m, 2H), 3.26 (q,J=7.32 Hz, 1H), 3.30-3.35 (m, 2H), 3.38-3.47 (m, 1H), 3.58-3.62 (m, 1H),3.69-3.73 (m, 2H), 3.99 (s, 2H), 7.00-7.07 (m, 1H), 7.12-7.18 (m, 2H),7.24 (dd, J=6.10, 2.14 Hz, 1H), 7.28-7.35 (m, 1H), 7.44-7.51 (m, 1H).

Example 763N-[2-(ethyl{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl]benzoyl}amino)ethyl]nicotinamide

To a suspension of EXAMPLE 719 as the HCl salt (59 mg, 0.134 mmol) in amixture of anhydrous tetrahydrofuran (2 mL) and acetonitrile (2 mL) wasadded triethylamine (0.056 mL, 0.403 mmol) and 2,5-dioxopyrrolidin-1-ylnicotinate (44 mg, 0.201 mmol). This suspension was heated at 60° C.overnight and concentrated. The residue was purified by HPLC (Zorbax,C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in H₂O: B: 0.1% TFA inCH₃CN; 0-100% gradient) to provide the title compound as the TFA salt.MS (DCI/NH₃) m/z 478 (M+H)⁺; ¹H NMR (CD₃OD) δ 1.08 (t, J=7.17 Hz, 3H),1.67-1.72 (m, 4H), 2.39-2.43 (m, 2H), 2.46-2.51 (m, 2H), 3.27-3.32 (m,2H), 3.44-3.53 (m, 1H), 3.73 (t, J=5.95 Hz, 1H), 3.79-3.84 (m, 2H), 3.97(s, 2H), 7.09-7.16 (m, 2H), 7.29-7.35 (m, 1H), 7.84 (dd, J=7.93, 5.49Hz, 1H), 8.51-8.57 (m, 1H), 8.81 (dd, J=10.99, 4.88 Hz, 1H), 9.08 (s,1H).

The foregoing is meant to be illustrative of the invention and not meantto limit it to disclosed embodiments. Variations and changes obvious toone skilled in the art are intended to be within the scope and nature ofthe invention as defined in the appended claims.

We claim:
 1. A method of treating leukemia, colon cancer, carcinomas ofthe breast, or cervical carcinomas in a mammal comprising administeringthereto a therapeutically acceptable amount of a compound of selectedfrom the group consisting of4-(3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2h)-one;4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)amino)-4-oxobutanoicacid; and1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)methyl)phenyl)pyrrolidine-2,5-dione;or a pharmaceutically acceptable salt thereof.
 2. A method according toclaim 1 additionally comprising radiotherapy.
 3. A method according toclaim 1 additionally comprising administering a chemotherapeutic agentselected from temozolomide, dacarbazine, cyclophosphamide, carmustine,melphalan, lomustine, carboplatin, cisplatin, 5-FU+/−leucovorin,gemcitabine, methotrexate, bleomycin, irinotecan, camptothecin, ortopotecan.